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of the 10th International Conference on Cachexia, Sarcopenia and Muscle
Wasting, Rome, Italy, 8–10 December 2017 (Part 1)
Version of Record online: 23 NOV 2017
How to Cite
(2017), Abstracts of the 10th International Conference on Cachexia,
Sarcopenia and Muscle Wasting, Rome, Italy, 8–10 December 2017 (Part 1).
Journal of Cachexia, Sarcopenia and Muscle, 8: 999–1080.
Body composition changes over three years in older adults: a descriptive longitudinal analysis
Maria Teresa Tomás1,3, Alejandro Galán-Mercant2,3 and Beatriz Fernandes1,3
1Escola Superior de Tecnologia da Saúde de Lisboa, Portugal; 2Universidade de Jaén, Spain; 32GHRG—Gerontology and Geriatric Health Research Group
Many studies analyse body composition changes in older adults. However,
few studies analyse body composition in elderly people with functional
measures. Studies using Double X-Ray analysis (DXA) or Bioimpedance
analysis proved to be reliable but expensive or only possible in a
The purpose of our study was to analyse
changes in body composition over three years using anthropometric
measures in a sample of elderly people in order to perceive functional
Methods: Forty-three participants (12 men; 31
women) aged 60 years and over and independent in activities of daily
life were assessed using anthropometric measures in a first moment and
past three years. Weight, height, waist and hip circumference were
measured, and body mass index (BMI) and waist-to-hip ratio (WHR) were
also calculated. Skeletal muscle mass (SMM) was also calculated using
Al-Gindan et al. (2014) equations and normalized for height to found
skeletal muscle index (SMI) in order to analyze cut-off points
associated with physical disability according to Janssen et al (2004).
Results: A significant difference was found over three years in SMM (p = 0.007), SMI (p = 0.027),
BMI (p = 0.041) and WHR (p = 0.003). The majority of the participants
has decreased SMM, SMI and BMI and increased WHR, which favors a worst
prognostic for comorbidities associated with these variables, and a
tendency for sarcopenic obesity seems to be present although more
studies are needed. Also, we found that using cut-off points for
disability risk 83.3% of the men and 38.7% of the women of our sample
were at moderate or high risk of disability. Three years later this
percentage has increased but only for women to 54.8%.
Although men are at risk of disability, women quickly lose their
functional capacity, making necessary a rapid intervention to reduce the
risk of disability in this population.
Prevalence of cachexia in dogs with congestive heart failure
Pamela L. Bay, Lisa M. Freeman and John E. Rush
Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA
Background and Aims:
Congestive heart failure (CHF) is a common, naturally occurring disease
in pet dogs that is often associated with cardiac cachexia, as defined
by a loss of muscle. One study of dogs with dilated cardiomyopathy (DCM)
and CHF showed that 54% of dogs were affected by cachexia. No studies
have been conducted to confirm these findings in dogs with DCM or to
assess prevalence in CHF from other forms of heart disease causing CHF.
Therefore, the aim of this study was to determine prevalence of cardiac
cachexia in dogs with CHF due to acquired heart disease.
Dogs with CHF evaluated by the Cardiology Service at the Cummings
School of Veterinary Medicine between June 2015 and June 2017 were
eligible. Dogs with DCM and myxomatous mitral valve disease (MMVD) were
enrolled. Data from the medical records were retrospectively reviewed,
including body weight, body condition score (BCS), and muscle condition
score (MCS). Body condition score, which assesses fat stores, was
measured on a 1–9 scale, with 1 = emaciated, 9 = obese, and 4–5
considered ideal. Muscle condition was categorized using the World Small
Animal Veterinary Association scoring system as normal muscle, mild
muscle loss, moderate muscle loss, or severe muscle loss.
Results: Median age of the dogs (n = 196) was 10.7 years (range, 1.7–18.0 years). Underlying diseases included MMVD (n = 168) and DCM (n = 28).
Mean body weight was 7.6 kg (range, 2.4–75.8 kg). Only 6.1% of dogs
were underweight (BCS < 4/9), and 41.8% of dogs were overweight or
obese (BCS > 5/9). However, muscle loss was identified in 48.0% of
dogs: Mild muscle loss: 73/196 (37.3%), moderate muscle loss: 14/196
(7.1%), and severe muscle loss: 7/196 (3.6%). 52.0% of dogs were
assessed to have normal muscle. Muscle condition score and BCS were not
significantly different between dogs with MMVD or DCM.
Conclusions: Although many dogs were overweight or obese, cachexia was present in 48% of dogs with CHF.
Comorbidities and mortality after cachexia hospitalization in Slovenia between 2004 and 2015
Daniel Omersa1, Jerneja Farkas2 and Mitja Lainscak2,3
1National Institute of Public Health, Ljubljana, Slovenia; 2General Hospital Murska Sobota, Murska Sobota, Slovenia; 3Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Cachexia is common in several chronic diseases and significantly
increases morbidity and mortality. There is a lack of data regarding
cachexia hospitalization burden and mortality after cachexia
hospitalization. Thus, we aimed to identify all patients that were
hospitalized due to cachexia and determine their mortality and
prognostic implications of different comorbidities.
The Slovenian National Hospitalization Database has been searched for
all individuals with main Cachexia hospitalization (ICD-10 codes: C80,
R64 and B22.2) between 2004 and 2015, and sex, age, length of stay and
comorbidities were recorded. For all patients with cachexia
hospitalization, date of death was recorded from Slovenian Death
Registry. Prevalence of comorbidities during cachexia hospitalization
were calculated and hazard ratios (HR) for mortality for sex, age and
patients' comorbidities were calculated using multiple Cox proportional
Results: Overall, we identified 1774 main
cachexia hospitalizations in 1406 patients. Main cachexia
hospitalizations contributed to 17.7% of all the hospitalizations of an
individual during the study period. Cancer, cardiovascular and pulmonary
diseases were the most prevalent in cachexia patients (62%, 27% and
10%, respectively). In-hospital mortality was 29%. Median survival for
discharged patients were 103 days (95% confidence intervals,
90–123 days). Older patients, those with cancer and pulmonary disease,
had significantly higher HR for mortality (1.16 for 10 year increase,
1.79 and 1.34, respectively).
hospitalized due to cachexia have extremely poor prognosis. Cancer,
which is the most prevalent comorbidity in patients hospitalized due to
cachexia, is associated with the worst prognosis.
Prevalence of cachexia among COPD cases in the ECLIPSE study
Merry-Lynn N. McDonald1,2, Erica Rutten3, Richard Casaburi4, Emiel F.M. Wouters3, Stephen I. Rennard5, David A. Lomas6, Bartolome Celli7, Alvar Agusti8, Ruth Tal-Singer9, Craig P. Hersh7,10 and Edwin K. Silverman7,10
1Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA; 3Centre of expertise for chronic organ failure, Horn, the Netherlands; 4Rehabilitation
Clinical Trials Center, Los Angeles Biomedical Research Institute at
Harbor Harbor-UCLA Medical Center, Torrance, CA, USA; 5Department of Medicine, Nebraska Medical Center, Omaha, NE, USA; 6Wolfson Institute for Biomedical Research, University College London, UK; 7Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA; 8Fundació
Investigació Sanitària Illes Balears (FISIB), Ciber Enfermedades
Respiratorias (CIBERES), Barcelona, Catalunya, Spain Thorax Institute,
Hospital Clinic, IDIBAPS, Univ. Barcelona, Barcelona, Spain; 9Respiratory R&D, GSK, Philadelphia, PA, USA; 10Channing Division of Network Medicine, Harvard Medical School, Boston, MA, USA
By population prevalence, there are more chronic obstructive pulmonary
disease (COPD) cases than cancer cases with cachexia. The consensus
definition of cachexia incorporates weight loss (WL) >5% in 12 months
in addition to 3 out of 5 of decreased muscle strength, fatigue,
anorexia, low fat-free mass index (FFMI) and abnormal biochemistry
(anemia, CRP, IL6, albumin). More recently, cancer cachexia has been
classified using WL >5% or, in the presence of low BMI or FFMI, WL
>2%. Further, the importance of pre-cachexia (WL ≤5%, anorexia and
inflammation) has been highlighted as more advanced cachexia may
indicate a refractory state. Thus, we aimed to examine the prevalence of
cachexia using these definitions in a cohort of COPD cases from the
Methods: A total of 1901 COPD cases were
assessed for cachexia. Annual weight, muscle strength, FFMI and anemia
data were analyzed. Fatigue and anorexia data were available at baseline
and end of study. CRP levels were measured at baseline and over the
first year. The consensus definition was coded at each annual visit an
individual participated in the study. Where data were not available for
the specific visit, an aggregate was created (e.g., ever had fatigue).
Participants who exhibited WL at an early visit with evidence it was
regained were coded as non-cachectic.
prevalence of cachexia based on the consensus definition ranged from
4.0% (Year 1) to 6.6% (Year 3). Over 3 years of the study, 11% of COPD
cases were classified as cachectic at some time point. The prevalence of
cachexia using the cancer cachexia definition ranged from 9.7% (Year 1)
to 17.7% (Year 3). The prevalence of pre-cachexia ranged from 2.0%
(Year 2) to 3.1% (Year 1).
Summary: Based on definition of cachexia and visit used, the prevalence in a large cohort of COPD cases ranged from 4.0% to 17.7%.
SARA-data: Integrated, real-time ICT Platform for the SARA interventional Clinical Trial in Age-related SARcopenia
Susanna Del Signore1,2, Waly Dioh2, Stefania Del Signore1 and Gianluca Zia1
1Bluecompanion ltd, London, UK; 2Biophytis, Paris, France
Introduction: SARA-Int(erventional), a randomized, double-blind clinical trial, will evaluate the safety and efficacy of two oral doses of SARconeos (BIO101) versus placebo over 6 months in 333 sarcopenic or obese sarcopenic patients Aged ≥65 years complaining of loss of strength and muscular function.
Methods: We deployed an integrated Information&Communication Technology (ICT) platform, SARA-data, to monitor on quasi
real-time different source data (clinical, imaging (DEXA), laboratory
and physical activity). Data can be generated at investigation sites, by
the centralised lab and by the patients themselves via wearable devices
and auto-evaluation questionnaires.
Bluecompanion implemented for
Biophytis SARA Data, which allows to collect and integrate on one
single web-based portal: an electronic Case Report Form (Clean WEB by
Telemedicine), participants row data from DEXA scans, and
biochemistry-haematology results from a centralised laboratory,
including sarcopenia-related biomarkers. Of note, continuous physical
activity recording is enabled during the whole clinical trial duration
by providing each older participant with a wrist-worn accelerometer. The
device transmits anonymised activity data to SARA platform via a
non-intrusive, unattended, home-centred machine-to-machine technology.
kind of high volume data, directly generated by the patient during
several months, fulfils the definition “Big data in health”,
encompassing “high volume, high diversity biological, clinical,
environmental, and lifestyle information collected from single
individuals to large cohorts, in relation to their health and wellness
status, at one or several time points” (Auffray C. et al.,
2016), and will constitute an important resource for additional,
supportive analyses complementing standardised muscular function
assessments. These data are generated in a real-life context and could
provide answers to specific questions by regulators and payers.
SARA-data are a single real-time ICT platform enabling data capture,
storage, analysis and retrieval of long-term clinical data generated
during SARA-Int, a randomized CT evaluating Sarconeos (Bio101) in
Age-related Sarcopenia, including Sarcopenic Obesity.
Changes of body weight and body composition and cachexia after stroke
Nadja Scherbakov1, Charlotte Pietrock1, Nicole Ebner2,3, Anja Sandek2,3, Miroslava Valentova2,3, Jochen B. Fiebach1, Joerg C. Schefold4, Stephan von Haehling2,3, Stefan D. Anker2,5, Kristina Norman6, Karl Georg Haeusler1,7 and Wolfram Doehner1,5
1Center for Stroke Research Berlin CSB, Charité - Universitätsmedizin Berlin, Berlin, Germany; 2Innovative
Clinical Trials, Department of Cardiology and Pneumology,
University Medicine Goettingen (UMG), Goettingen, Germany; 3German Centre for Cardiovascular Research (DZHK), partner site Goettingen, Goettingen, Germany; 4Department of Intensive Care Medicine, Inselspital, Bern University Hospital, Switzerland; 5Department of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany; 6Research Group on Geriatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany; 7Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Background and Purpose:
Body weight loss after stroke has been shown in several clinical
trials. Cachexia after stroke has not been studied systematically yet.
The purpose of this prospective study was to investigate dynamical
changes of body composition and body weight one year after ischemic
stroke, and its association with functional outcome.
Methods: 67 consecutive patients with acute ischemic stroke (age 69 ± 11 years, BMI 27 ± 4 kg/m2)
with mild to moderate neurological deficit (mean NIHSS 4.3, range 0–12)
were analyzed. Body composition was examined by dual energy X-ray
absorptiometry (DEXA) in acute phase (4 ± 2 days) and at 1-year
follow-up (389 ± 26 days). Cachexia was defined according to consensus
definition by body weight loss ≥5% within one year and clinical
symptoms. Functional assessments included Barthel Index (BI), modified
Rankin scale (mRS), and muscle strength tests.
Cachexia was diagnosed in 21% of the patients at 1-year follow-up. Most
changes of body composition concerned the fat tissue with the highest
fat mass decline of 12.5% in cachectic patients, followed by 5% loss in
non-cachectic patients with weight loss, and fat mass increase by 8% in
patients with weight gain. In addition, cachectic patients lost 3% of
the lean mass (P < 0.05).
At baseline patients who
developed cachexia during follow up were older (75 ± 9 years), had
moderate neurologic deficit (mean NIHSS 5.8), and the lowest physical
and functional capacity. They remained with the worse functional
impairment (mRS 2.1 ± 1.6, P < 0.05, Barthel Index 74 ± 36, P = 0.002) and handgrip strength (22.4 ± 14.9 kg, P < 0.05)
compared to other patients at 1-year FU. After adjustment for multiple
confounders, patients with higher functional impairment (OR 1.87, 95% CI
1.09–3.20) and neurologic deficit (OR 3.63, 95% CI 0.97–13.6) were at
risk for cachexia.
Conclusions: The most changes of body
composition after stroke with mild-to-moderate neurologic deficit
concerned the fat tissue. Attention should be focused on identification
and targeting of cachexia in the early phase following the stroke.
a new strategy to evaluate body composition in crohn's patients
undergoing hematopoietic stem cell transplantation (HSCT)
Andrea Z. Pereira1, Sandra E.A. Gonçalves1, Bianca L. de Sá2, Marister Cocco3, Andreza A.F. Ribeiro1 and Nelson Hamerschlak1
1Oncology and Hematology Department, Hospital Israelita Albert Einstein, S. Paolo, Brazil; 2Nutrition Department, Hospital Israelita Albert Einstein, S.Paulo, Brazil; 3Physiotherapy Department, Hospital Israelita Albert Einstein, S.Paulo, Brazil
Crohn disease is a chronic inflammatory disorder of the
gastrointestinal tract with a strong polygenic immune component. In
refractory cases, autologous HSCT can decrease disease activity and
mucosal healing and improve quality of life. Reduced muscular mass and
excess visceral fat in patients undergoing HSCT are associated with
higher mortality, longer hospitalization, longer use of
immunosuppressive drugs, graft-versus-host disease, shorter disease-free
interval after the HSCT and comorbidities leading to shorter survival
Objectives: To evaluate muscle thickness and visceral fat by US.
We evaluated 5 HSCT patients (≥18 years) at Hospital Israelita Albert
Einstein, São Paulo, Brazil, on their first day of hospitalization,
before HSCT and after the engraftment. The thickness of the right
femoral quadriceps muscle (RFQ), measured at 6 cm from the top edge of
the patella was measured using US in B-mode. The VF was measured in the
abdominal region, by the thickness of the fat layer between the linea
alba and the anterior wall of the aorta.
patients were men (75%) with a mean age of 35 years (±14 years). Most
patients were undernutrition, with body mass index (BMI) of 21 kg/m2 (±2.5 kg/m2).
The average time EN was 11 days (±1 day). In the baseline, RFQ was
1.5 cm (±0.2 cm), and the VF was 4.2 cm (±1.3 cm). After engrafment, RFQ
was 1.3 cm (±0.2 cm), and the VF was 4.2 cm (±1.2 cm). There wasn't
significant difference between baseline and after engraftment, although
RFQ had reduced in all patients.
Conclusions: In this
cohort of patients, we found reduced muscle thickness after engraftment,
and VF didn't have any alterations. The US was a practical, economical
and effective method to evaluate these patients.
Elderly patients undergone hematopoietic stem cell transplantation: body composition and engraftment
Andrea Z. Pereira1, Ludmila M. Koch1, Polianna M.R. Souza1, Bianca L. de Sá2, Andreza A.F. Ribeiro1 and Nelson Hamerschlak1
1Oncology and Hematology Department, Hospital Israelita Albert Einstein, S.Paulo, Brazil; 2Nutrition Department, Hospital Israelita Albert Einstein, S.Paulo, Brazil
Hematopoietic Stem Cell Transplantation (HSCT) in elderly is a
brand-new issue. Changes in body composition after HSCT have been the
subject of previous studies; however, there aren't many studies in
Objectives: To evaluate muscle thickness
and visceral fat by US; % muscle mass, % fat mass and phase angle by
BIA. To correlate body composition with engraftment (EN).
In this prospective study, we evaluated 16 HSCT patients (≥60 years) at
Hospital Israelita Albert Einstein, São Paulo, Brazil, on their first
day of hospitalization, before HSCT and after the EN. The thickness of
the right femoral quadriceps muscle (RFQ), measured at 6 cm from the top
edge of the patella was measured using ultrasound (US) in B-mode,
transversal plane. The visceral fat (VF) was measured in the abdominal
region, by the thickness of the fat layer between the linea alba and the
anterior wall of the aorta. The % muscle mass (MM), % fat mass (FM) and
phase angle (PA) were evaluated by Bioimpedanciometry(BIA).
Most patients were men (75%) with a mean age of 64(±5.0 years). We had
50% of autologous HSCT and 50% allogenic HSCT. The mean time EN was
13(±4 days). In the baseline, weight was 80(±17 kg), RFQ was
1.8(±0.3 cm) and the VF was 5.5(± 2.0 cm); %MM was 68.5(±11); %FM was
27.5(±7.5); PA was 5.3((±0.7). After EN, weight was 73(±13 kg). RFQ was
1.5(±0.3 cm) and the VF was 5,0(±2.2 cm); %MM was 55.5(±20.5); %FM was
25(±7.0); PA was 7.4(±0.8). There wasn't significant difference between
baseline and after engraftment, although all measurements had reduced in
all patients, exception for PA and VF had increased. We found the
negative correlation between engraftment and RFQ(rp: −0,6),
independently of HSCT type by regression. (rp: −0,6).
In this cohort of patients, muscle thickness and mass was reduced, and
visceral fat and phase angle was increased after engraftment. The higher
muscle thickness correlated faster engraftment.
Elderly quilombolas: Prevalence of sarcopenia using algorithm proposed by the European working group on sarcopenia in older people.
Prognostic value of psoas muscle area and density in patients undergoing cardiovascular surgery
Masashi Yamashita1, Kentaro Kamiya1,2, Atsuhiko Matsunaga1,2, Tadashi Kitamura3, Nobuaki Hamazaki4,5, Ryota Matsuzawa4, Kohei Nozaki4, Shinya Tanaka5, Junya Ako6 and Kagami Miyaji3
1Department of Rehabilitation Sciences, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan; 2Department of Rehabilitation, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan; 3Department of Cardiovascular Surgery, Kitasato University School of Medicine, Sagamihara, Japan; 4Department of Rehabilitation, Kitasato University Hospital, Sagamihara, Japan; 5Department of Cardiovascular Medicine, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan; 6Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
Low skeletal muscle area and density, as determined by computed
tomography (CT), have yet to be examined and compared in terms of
prognostic capability in patients requiring open cardiovascular surgery.
This study was performed to examine whether psoas muscle area and
density are associated with postoperative mortality and physical
performance in patients undergoing cardiovascular surgery.
We reviewed the findings in 773 consecutive patients undergoing
preoperative CT imaging including the level of the third lumbar vertebra
for clinical purposes. Skeletal muscle area was calculated from psoas
muscle cross-sectional area (CSA) on preoperative CT images at the level
of the third lumbar vertebra divided by the square of the patient's
height to give the skeletal muscle index (SMI: cm2/m2).
Skeletal muscle density determined by muscle attenuation (MA) was
calculated by measuring the average Hounsfield units of the psoas muscle
CSA. Quadriceps strength and 6-minute walking distance were examined as
indices of physical performance.
Results: The mean age of
the study population was 68.6 ± 14.0 years, and 64.7% of the patients
were male. Multivariate Cox regression analysis showed that low MA
(hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.14–4.16, P = 0.018), but not low SMI (HR, 1.35; 95% CI, 0.71–2.56, P = 0.361),
was significantly associated with all-cause mortality. Kaplan–Meier
analysis showed that low MA, but not low SMI, predicted poor prognosis (P = 0.014).
Correlation analysis indicated that MA was more strongly associated
with quadriceps strength and 6-minute walking distance than SMI.
Conclusions: Low skeletal muscle density, but not skeletal muscle area, predicted survival in patients undergoing cardiac surgery.
The usefulness of body weight for predicting skeletal muscle mass in congested state of heart failure outpatients
Shunichi Doi1, Norio Suzuki1, Keisuke Kida2, Chikayuki Ito3, Kohei Ashikaga3, Kengo Suzuki2, Hisao Matsuda1, Tomoo Harada2 and Yoshihiro J. Akashi2
of Cardiology, Department of Internal Medicine, St. Marianna University
School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan; 2Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; 3Division of Cardiology, Department of Internal Medicine, Kawasaki Municipal Tama Hospital, Kawasaki, Japan
Body mass index is cited as an index to recognize significant
correlation with skeletal muscle mass. However, body weight changes due
to edema are often observed in chronic heart failure (CHF). We
investigated the usefulness of body weight for evaluating skeletal
muscle mass wasting in congested CHF outpatients.
Totally 45 CHF outpatients with brain natriuretic peptide (BNP)
≥200 pg/ml were enrolled. Total skeletal muscle mass was measured at the
level of the third lumbar vertebra using available preoperative
computed tomography images (Cutoff value: male 36.2cm2/m2, female 29.6cm2/m2). It was investigated on the relationship between skeletal muscle mass and each nutritional indicator.
Results: The mean age was 75.6 ± 6.4 years old, body mass index (BMI) was 22.4 ± 2.9 kg/m2
and left ventricular ejection fraction was 44.3 ± 18.9%. Median BNP was
417.5 pg/ml (interquartile range, 271.1–590.8). Of the study patients,
53.3% patients were male, 26.7% patients had ischemic heart failure,
57.8% patients had New York Heart Association (NYHA) classification ≥2,
and 68.9% patients had Mini Nutritional Assessment Short Form (MNA-SF)
score ≤ 11. Correlation between skeletal muscle mass and each index was
BMI (r = 0.51, p < 0.01), Geriatric Nutritional Risk Index (GNRI; r = 0.42, p = 0.04), MNA-SF(r = 0.28, p = 0.15) and serum albumin value (Alb; r = −0.06, p = 0.77).
The logistic regression analysis indicated that the odds ratio, in BMI,
was 0.66 (95% confidence interval; 0.48–0.85, p < 0.01) and area
under the receiver operating characteristic curve (AUC) was 0.76,
suggesting that BMI might be independent predictors for muscle mass
Conclusions: Though the congested state of CHF
outpatients, it was suggested the usefulness of body weight for
predicting skeletal muscle mass.
of height-, weight-, body surface area-, and body mass index-adjusted
muscle mass indices for prediction of physical performance in Korean
Jun Chul Kim1, Jun Young Do2, Kyu Hyang Cho2 and Seok Hui Kang2
of Nephrology, Department of Internal Medicine, CHA Gumi Medical
Center, CHA University, Gumi, Gyeongsangbuk-do, Republic of Korea; 2Division of Nephrology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea
Our study aims to evaluate the association between height-, weight-,
body surface area- (BSA), or body mass index- (BMI) adjusted muscle mass
indices and physical performance in Korean hemodialysis patients.
Methods: Patients were included if they were on HD for ≥6 months (n = 84).
Each patient's appendicular skeletal muscle mass (ASM, the sum of both
upper extremities and lower extremities) was measured by dual X-ray
absorptiometry. ASM was adjusted to body weight (BW, kg), height2 (Ht2, m2), BSA (m2), or BMI (kg/m2).
Low muscle mass was defined as muscle mass of 2SD below sex-specific
means of healthy young adults (20–29 years). Each participant performed a
gait speed test (GS), a hand grip strength (HGS) test, a sit-to-stand
test performed 5 times (5STS), a sit-to-stand for 30 second test
(STS30), a 6-minute walk test (6MWT), a timed up and go test (TUG), and
an average steps count (AS).
Results: In men, Pearson's correlation coefficients for GS, 5STS, STS30, 6-MWT, TUG, and AS were highest in ASM/Ht2.
Results from partial correlation or linear regression analyses
displayed similar trends to those derived from Pearson's correlation
analyses. ASM/Ht2 had the greatest negative predictive value
for low GS. Patients with low muscle mass had significantly lower
physical performances (HGS, 5STS, 6MWT, TUG) than those with normal
muscle mass by ASM/Ht2. In women, the association between muscle mass indices and physical performance was lack.
Conclusions: Height adjusted muscle mass may be the best for predicting physical performance in men on hemodialysis.
Prevalence and progression of limb contractures amongst long-term care residents: data from a 5-year observational study
Kuen Lam1, Joseph Kwan2, Chi Wai Kwan3 and Iris Chi4
1Cheshire Home, Shati, Hong Kong; 2Department of Medicine, The University of Hong Kong, Hong Kong SAR; 3Department of Statistics and Actuarial Science, The University of Hong Kong; 4Suzanne Dwork-Peck School of Social Work, University of Southern California, Los Angeles, CA, USA
Limb contractures are associated with poor outcomes and quality of life
in long-term care facility (LTCF) residents. We aimed to study the
prevalence and progression of limb contractures over a 5-year follow-up
period amongst LTCF residents in Hong Kong.
the Hong Kong Longitudinal Study on LTCF Residents between 2005 and
2015, we analyzed the data for residents who had assessment from the 1st
up to 5th year since admission. Trained nurses, social workers and
therapists utilized the Minimum Data Set Resident Assessment Instrument
(MDS-RAI 2.0) in 10 residential LTCFs. Limb contractures were defined as
functional limitation in the range of motion involving the upper or
lower limbs. Primary outcomes were annual prevalence and time trend of
limb contractures over 5 years.
Results: We analyzed the
data for 1,736 older residents (611 men, mean age 83.2 years). During
the first 5 years since admission, the annual prevalence of upper limb
contractures increased from 30% to 36%, and lower limb contractures
increased from 41% to 56%. Time trends were as follows: the proportion
of residents who had no contractures on admission remained
contracture-free after 5 years was 59.7% for upper limbs and 39.8% for
lower limbs, while the proportion of residents who had developed new
contractures after 5 years was 15.1% for upper limbs and 26.5% for lower
limbs. The proportion of residents who had unilateral contractures on
admission which had improved after 5 years was 4.1% for both upper limbs
and lower limbs, and the proportion of residents who had either
unilateral or bilateral contractures on admission which did not change
after 5 years was 21.2% in upper limbs and 29.6% in lower limbs.
Joint contractures are highly prevalent amongst residents admitted to
the LTCF, and many residents develop new or worse contractures during
the first 5 years of their admission. Further studies are needed to
identify the potential strategies to prevent functional decline in this
Validating the Care Assessment Need (CAN) tool for frailty screening
Shivani Priyadarshni1, Zubair Rahaman1, Kimberly Cabrera1, Stuti Dang1,2, Willy Valencia1, Ramankumar Anam1, Michael J. Mintzer1 and Jorge G. Ruiz1,2
1Miami VAHS Geriatric Research Education and Clinical Center; 2Clinical Center and University of Miami Miller School of Medicine
Frailty is a state of vulnerability to stressors resulting in higher
morbidity, mortality and healthcare utilization in older adults.
Multiple instruments are used to measure frailty; most are
time-consuming. The Care Assessment Need (CAN) score is automatically
generated from electronic health record data using a statistical model;
it is expressed as a percentile, ranging from 0 (lowest risk) to 99
(highest risk). The CAN score is a known predictor of high risk for
hospitalization and mortality at 90 days and one year. The purpose of
the study was to validate the CAN score as a screening tool for frailty
among older adults in clinical practice.
cross-sectional study compared the CAN score with a reference standard.
The reference standard, a 40-item Frailty Index, was generated using
retrospective data collected during a Comprehensive Geriatric Assessment
(CGA) performed by geriatric medicine physicians. To assess the ability
of the CAN score to correctly identify frailty, we calculated the
sensitivity, specificity, positive predictive value (PPV), negative
predictive value (NPV) and diagnostic accuracy (assessed by the area
under the receiver operating characteristic (ROC) curve).
184 patients over age 65 were included in the study: 98% male, 61%
White, 80% non-Hispanic. Our CGA-based Frailty Index defined 13% as
robust, 55% as prefrail and 32% as frail. For the frail, statistical
analysis demonstrated that a threshold CAN score of 52.5 provides
sensitivity, specificity, PPV and NPV of 91%, 40%, 27%, and 95%,
respectively. Area under the ROC curve was 0.749 (SD = 0.038, p = 0.0005, 95% CI = 0.674–0.823).
CAN score is a potential screening tool for frailty among older adults
as it is generated automatically and provides acceptable diagnostic
accuracy. Hence, CAN score may offer useful information to Primary Care
Providers for early clinical interventions.
variations of skeletal muscle mass and strength among Italian and
Taiwanese community-dwellers: results from the Milan-EXPO survey and the
I-Lan Longitudinal Aging Study
Francesco Landi1, Matteo Tosato1, An-Chun Hwang2,3, Liang-Kung Chen2,3, Li-Ning Peng2,3, Riccardo Calvani1, Anna Picca1, Roberto Bernabei1 and Emanuele Marzetti1
1Department of Geriatrics, Neurosciences and Orthopedics, Catholic University of the Sacred Heart, Rome, Italy; 2Aging and Health Research Center, National Yang Ming University, Taipei, Taiwan; 3Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan
Age- and gender-specific curves of muscle mass and strength, using data
from large samples of community-dweller people, need to be better
established and so are possible differences among ethnic groups. The
aims of the present study were to analyze age- and gender-specific
changes in measures of muscle and strength among community-living
persons and to identify differences between Caucasian and Asiatic
Methods: The Italian survey (“Longevity
Check-up”), conducted during EXPO 2015 in Milan, consisted of a
population assessment aimed at evaluating the prevalence of specific
health metrics in persons outside of a conventional research setting (n = 1924),
with a special focus on muscle mass and strength. The Taiwanese survey
used the first-wave sampling from the I-Lan Longitudinal Aging Study
(ILAS) collected from August 2011 to August 2013 (n = 1839).
Muscle mass was estimated by using calf circumference of the dominant
side. Muscle strength was determined through handgrip strength testing.
The mean age of the 1924 Italian participants was 62.5±8.3 years, of
whom 1031 (53.6%) were women. Similarly, the mean age of the Taiwanese
sample was 63.9±9.3 years with 966 (52.5%) women. Overall,
cross-sectional observations suggest that calf circumference decline
with age in both genders. The calf circumference was significantly
greater among Italian participants compared with Taiwanese people in all
age groups. A similar effect of age was observed for muscle strength.
As for calf circumference, muscle strength was significantly greater
among Italian persons relative to Taiwanese participants.
Muscle mass and strength curves for Caucasian and Asiatic people may be
used to derive reference values for subsequent use in research and
clinical settings. In particular, the analyses of trajectories of muscle
parameters may help identify cutoffs for estimating risk of adverse
events as well as the optimal timing for intervening.
Associations between lean mass, strength and mortality in the elderly: the EXERNET study
Lucía Sagarra-Romero1,2, Alejandro González-Agüero3,4,5,6, David Navarrete-Villanueva3,5, Alejandro Gómez-Bruton3,4,7, Angel Matute-Llorente3,4, José A. Casajús3,4,5,6, Ignacio Ara2,8, Germán Vicente-Rodriguez3,4,5,6 and Alba Gomez-Cabello3,4,5,8,9
1VALORA Reseach Group, Universidad San Jorge, Spain; 2GENUD Toledo Research Group, Universidad de Castilla-La Mancha, Toledo, Spain; 3GENUD (Growth, Exercise, NUtrition and Development) Research Group, Universidad de Zaragoza, Spain; 4Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Spain; 5Instituto Agroalimentario de Aragón (IA2); 6Faculty of Health and Sport Sciences (FCSD), Department of Physiatry and Nursing, University of Zaragoza, Zaragoza, Spain; 7Universidad Isabel I, Burgos, Spain; 8Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Spain; 9Centro Universitario de la Defensa, Zaragoza, Spain
Introduction: Negative changes in lean mass (LM) and muscle strength (MS) have been shown to occur across the aging process .
These changes are linked with morbidity and have a negative effect on
physical ability and independence in older adults and also increase risk
of falls. However, the link between LM and mortality in the elderly is
Purpose: The aim of this study was to investigate the relationship between LM, MS and mortality in the elderly.
In this prospective longitudinal study a total of 223 seniors (64 men
and 159 women) (age 73 ± 5.8 years) were evaluated in Zaragoza-Aragon
(Spain) during 2008, as part of the elderly EXERNET multi-centre study .
Whole body muscle mass was measured with dual energy X-ray
absorptiometry (kg). MS of upper and lower extremities was assessed
using two tests from the “Senior Fitness Test”: “Chair Stand Test” and
“Arm Curl Test”. Access to mortality data was obtained from the Spanish
Statistical Office (INE) register in 2017. The Mann–Whitney U test was
used to compare differences between groups (deceased vs alive).
Results: There were 19 deaths among the original participants.
The mean total LM was 55.5 kg in men and 39.9 kg in women. No
association was found between LM and mortality. However, MS in lower and
upper body were statistically lower (p < 0.05) in the
deceased group (12.7 ± 4.4 and 13.3 ± 4.9, respectively) compared with
those still alive (14.3 ± 3.1 and 16.2 ± 3.8, respectively). These
differences were maintained after adjustment for daily sitting time.
Lean mass is not associated with mortality in elderly people. However,
there is an inverse association between muscular strength and mortality
suggesting that functionally rather that the size of the muscle seems
related to mortality.
Acknowledgements: The elderly EXERNET
multi-centre study has been supported by IMSERSO (104/07 and 147/2011),
University of Zaragoza (UZ 2008-BIO-01), Centro Universitario de la
Defensa de Zaragoza (UZCUD2016-BIO-01), Ministerio de Economía,
Industria y Competitividad (DEP2016–78309-R), Biomedical Research
Networking Center on Frailty and Healthy Aging (CIBERFES) and FEDER
funds from the European Union (CB16/10/00477). The authors are also
grateful to all the volunteers and to the Community Center for Seniors
Pedro Laín Entralgo (Zaragoza), whose cooperation and dedication made
this study possible.
- 1Strength and muscle mass loss with aging process. Age and strength loss. Muscles, ligaments and tendons journal. 2013 Oct;3(4):346–50. PubMed PMID: . Pubmed Central PMCID: 3940510., .
of overweight and obesity in non-institutionalized people aged 65 or
over from Spain: the elderly EXERNET multi-centre study. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2011 Aug;12(8):583–92., , , , , , et al.
Prevalence of sarcopenia in elderly residents in the urban and rural area of the south region of Brazil
Letícia Mazocco1, Maria Cristina Gonzalez2, Thiago G. Barbosa-Silva3 and Patrícia Chagas1,4
1Postgraduate Program in Gerontology at the Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil; 2Postgraduate Program in Health and Behavior at the Universidade Católica de Pelotas (UCPEL), Pelotas, RS, Brazil; 3Postgraduate Program in Epidemiology of the Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil; 4Department of Food and Nutrition at the Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil
The sarcopenia is a syndrome characterized by the progressive and
generalized loss of skeletal muscle mass and strength. The aim of this
study was to evaluate the prevalence of sarcopenia in a convenience
sample of elderly women submitted to bone densitometry and living in the
urban and rural area in the South of Brazil.
is a cross-sectional study with elderly (over 60 years old) who
performed bone densitometry. Sarcopenia was defined according to the
criteria recommended by the European Working Group on Sarcopenia in
Older People (EWGSOP): muscle mass was evaluated through the Dual-energy
X-Ray absorptiometry, muscle strength was measured by using the
handgrip strength, and muscular performance was assessed through the 4 m
gait speed test. Sociodemographic data was evaluated through a specific
Results: A total of 205 elderly women with a
mean age of 67.3 ± 5.9 years were included in the study, the majority
living in rural areas (65.9%), aged 60–69 years (66.3%), Caucasian
(71.2%), with 4 to 8 years of schooling (47.3%), with partner (61.5%)
and retired (92.2%). The prevalence of sarcopenia was 2.4% of the total
sample (5 subjects), with a significant higher prevalence in the urban
area (5.1%) when compared to the rural area (0.7%), (p = 0.047). There was a significant association with the living area (urban × rural) and schooling (p < 0.001), occupation (p = 0.010), socioeconomic status (p = 0.001) and smoking (p = 0.006).
The environment in which the elderly women lived was independently
associated with sarcopenia OR = 9.561 (95%CI: 1.021–89.523) (p = 0.048).
The prevalence of sarcopenia was significantly higher in the urban
elderly than in rural women. After multivariate analysis, the residence
was still independently associated with sarcopenia.
In a sample of elderly women of the south region of Brazil, 2.4% of the
total sample presented sarcopenia. Residence was independently
associated with sarcopenia, showing a greater chance of sarcopenia in
the urban elderly.
difference in anemia association with physical function in
community-dwelling Korean elders: results from the Korean Longitudinal
Study on Health and Aging (KLoSHA)
Hoon Hoon Lee1, Seung Yeol Lee2, Nam-Jong Paik1,3 and Jae-Young Lim1,3
1Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; 2Department
of Rehabilitation Medicine, Soonchunhyang University Bucheon Hospital,
Soonchunhyang University College of Medicine, Bucheon, South Korea; 3Department
of Rehabilitation Medicine, Department of Rehabilitation Medicine,
Seoul National University College of Medicine, Seoul, South Korea
Anemia is common in old age, and the prevalence increases with aging.
It is known that the physical performance declines with aging, and
anemia is associated with the frailty, but whether gender factor affects
functional decline is still controversial. The aim of this study is to
find out the different associations of anemia with muscle strength and
physical performance between old-men and old-women.
We recruited baseline data from a population-based cohort study on
old-aged Koreans, known as ‘the Korean Longitudinal Study on Health and
Aging’ (KLoSHA). A total of 542 people aged 65 years and above were
included. Data regarding age, gender, hemoglobin level, body weight,
height, body mass index (BMI), physical activity score, muscle strength,
muscle mass, pain related dysfunction (WOMAC-K), depressive symptoms
(GDS-K), global cognition (MMSE), comorbid conditions and physical
performance measure with short physical performance battery (SPPB) were
included and analyzed.
Results: Skeletal muscle mass,
strength and SPPB were highly associated with anemia. SPPB of old-women
with anemia was lower than those without anemia (7.76 ± 2.47 vs
8.93 ± 2.53), but there's no definite difference in strength whether
anemia presents or not (43.1 ± 19.5 Nm vs 48.4 ± 16.9 Nm). In contrast,
old men with anemia and without anemia showed similar SPPB (9.44 ± 2.19
vs 9.95 ± 2.26), but the strength of men with anemia was significantly
lower than that without anemia (62.4 ± 22.8 Nm vs 79.8 ± 27.1 Nm). In
the multivariate linear regression analysis, SPPB of both men and women
with anemia related with only WOMAC-K, while one without anemia has
multiple related variables with such as MMSE, Age and physical activity
other than WOMAC-K.
Conclusions: We found out that anemia
associated differently with muscle strength and physical performance
between old men and old women. Additionally, managing pain along with
treatment of anemia in both old men and women may be key source in
developing model for promoting better health.
Sarcopenia, obesity and metabolic syndrome
Gloria Gabriela Peña Ordóñez1, Lilia Patricia Bustamante Montes2, Ninfa Ramirez Duran3 and Alfonso José Cruz Jentoft4
1Universidad Autonoma del Estado de Mèxico, Toluca, 50180, Mexico; 2Universidad Autonoma de Guadalajara; 3Universidad Autonoma del Estado de Mexico; 4Hospital Universitario Ramon y Cajal
Sarcopenia is a geriatric syndrome that increases the risk of falls and
severe fractures, physical dependence and death. The relationship
between obesity, muscle and its function, as well as the effect on its
metabolism are important to understand sarcopenia because the body fat
affects the metabolism and muscle. In Mexico over 70% of the adult
population is overweight. The objective of this study is to evaluate the
association between sarcopenia, obesity and metabolic syndrome.
Observational, analytical, prospective study of cases and controls
incident in 2016 and 2017. Sampling is done for convenience in subjects
older than 60 years of the Geriatric Care Clinic (ISEM). Clinical
records were reviewed to obtain biochemical and sociodemographic data;
diagnostic tests for Sarcopenia (percentage of bioelectrical impedance
muscle mass, hand grip and short battery of physical tests, SPPB) were
Data were analyzed using non-conditional multiple
logistic regression models to obtain the odds ratios (OR), (confidence
intervals calculated at 95%).
Results: 97 patients were
recruited, of which 62 were cases and 35 controls. The higher weight was
found in controls (72.9 kg DE +/− 11.4 vs. to 68.8 kg DE +/− 12.2).
However, mean body mass index (BMI) and fat percentage were higher in
cases than in controls. In cases with severe sarcopenia, it was observed
more fat than muscle (mean of 8.6 kg).
There was a cut of the
total patients (35 cases/35 controls) to obtain preliminary results,
founding that for each unit that increase the fat percentage, the risk
to sarcopenia increase 30%. The rest of the 27 controls will be added to
the study in August.
Conclusions: Excess body fat reduces
the quality of muscle function, especially strength, probably by fat
infiltration in the muscle. However sarcorpenia in elderly is related
with overweight and desnutrition.
quilombolas: prevalence of sarcopenia using algorithm proposed by the
European working group on sarcopenia in older people
Sinésio Silva Neto, Margô Gomes de Oliveira Karnikowski, Neila Barbosa
Osório, Leonardo Costa Pereira, Liana Barbaresco Gomide and João Paulo
University of Federal Tocantins, Palmas, Brazil
Sarcopenia is considered a geriatric syndrome. Currently, there is no
agreed definition of sarcopenia, so it is still a challenge to establish
the actual prevalence of sarcopenia in the elderly in different
races/ethnicities, especially in elderly quilombolas.
Identify sarcopenia in the elderly living in maroon settlement using
the algorithm proposed by the European Working Group on Sarcopenia in
Patients and Methods: This is a
cross-sectional study with 70 participants (SD 65.58 ± 6.67 years) men
and women living in the Quilombo communities called Malhadinha and
Córrego Fundo, located in the city of Brejinho Nazaré-Tocantins-Brazil.
For the diagnosis of sarcopenia we used the recommendations proposed by
the European Working Group on Sarcopenia in Older People. Muscle mass
was analyzed by the Dual-energy X-ray absorptiometry and the handgrip
strength by hand dynamometer. The physical performance was analyzed
using the walking speed test. We used the SF-36 questionnaire to analyze
the quality of life.
Results: We identified a prevalence
of sarcopenia of 10% in the sample. The sarcopenic individuals were
classified as low handgrip strength. All individuals in the sample had
adequate physical performance.
Conclusions: We conclude
that the identification of the prevalence of sarcopenia in the elderly
maroons was high. The algorithm proposed by the European Working Group
on Sarcopenia in Older People had clinical applicability in the study
Association between sarcopenia and quality of life in quilombola elderly in Brazil
Sinésio Silva Neto, Margô Gomes de Oliveira Karnikowski, Neila Barbosa
Osório, Leonardo Costa Pereira, Liana Barbaresco Gomide and João Paulo
University of Federal Tocantins, Palmas, Brazil
has a direct and indirect impact on the quality of life of elderly
populations of different races and ethnicities. No study has yet
analyzed these variables in populations of elderly people of the
“quilombola” ethnic group.
Objective: We aimed to verify
the association between sarcopenia and quality of life in quilombola
elderly using the Baumgartner and the EWGSOP criteria.
This was a cross-sectional study of 70 male and female participants.
Quality of life was evaluated using the multidimensional SF-36 of the
Medical Outcomes Study. Sarcopenia was diagnosed according to the
Baumgartner cutoff for appendicular skeletal muscle mass and the
criteria recommended by the EWGSOP. Muscle mass and fat mass percentages
were analyzed by DXA, while handgrip strength (HGS) was evaluated using
a hand-held dynamometer. Physical performance was assessed through a
gait speed test.
Results: The prevalence of sarcopenia was
15% according to the Baumgartner cutoff and 10% according to EWGSOP
criteria. Quilombola elderly classified as physically active or very
active were at least six times less likely to develop sarcopenia than
those classified as irregularly active or sedentary. HGS was negatively
associated with a diagnosis of sarcopenia according to both sets of
criteria. Subjects with sarcopenia reported lower scores than those
without the condition on the physical role functioning and bodily pain
domains of the SF-36.
Conclusion: In this sample of
quilombola elderly, quality of life was negatively associated with
sarcopenia, regardless of the classification criteria used.
Additionally, the results showed that diagnostic criteria for sarcopenia
should include reductions in lean mass in addition to measures of
functioning and physical performance because some subjects showed the
former symptom without any alteration of the latter two variables.
Quantitative assessment of muscle in cats using ultrasound
Lisa M. Freeman, James Sutherland-Smith, Charles O. Cummings and John E. Rush
Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA
Background and Aims:
Cachexia occurs in cats with naturally occurring heart failure, kidney
disease, cancer, and other chronic diseases. Muscle loss can be assessed
subjectively using a muscle condition score, but is difficult to
quantify in cats as CT and DEXA require general anesthesia. Therefore,
non-invasive methods for quantifying muscle loss are needed. We
previously quantified an ultrasound technique of muscle normalized with
vertebral size in dogs. The goal of this study was to assess this
technique in cats.
Methods: Thirty healthy pet cats between
1 and 6 years of age were enrolled in the study. All cats were neutered
and in ideal body condition. Transverse ultrasound images of epaxial
muscle height (mean, 3 measurements each side) were obtained at the 13th
thoracic vertebra using a 12–5 Mhz linear transducer. Fourth thoracic
vertebral (T4) length was measured from a thoracic radiograph and the
ratio of the epaxial muscle height to T4 length was calculated and
compared to body weight using the Pearson correlation coefficient.
One cat was identified to have a cardiac murmur, so 29 cats completed
the study. Mean body weight was 5.05 ± 1.40 kg (range, 2.23–8.05 kg).
Mean epaxial muscle height = 1.27 ± 0.13 cm which was significantly
correlated with body weight (r = 0.65; P < 0.001). The ratio of epaxial muscle height to T4 length was not correlated with body weight (r = −0.18; P = 0.34). The range of values for the ratio of epaxial muscle height to T4 length in healthy pet cats was 0.93–01.55.
Since the ratio of epaxial muscle height to T4 was independent of body
weight, it appears to be a good way of normalizing muscle size across
cats of different body weights. Studies assessing this method in cats of
different levels of adiposity and in those with cachexia and sarcopenia
Decreased muscle CT attenuation in old dogs
James Sutherland-Smith, Dana Hutchinson and Lisa M. Freeman
Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, 01536, USA
Background and Aims:
Sarcopenia has been documented in aging dogs by CT, DEXA, and
ultrasound. In addition to reductions in muscle mass, qualitative
changes in muscle also occur during aging in humans, but changes in
muscle density have not been documented in dogs. Therefore, the
objective of this study was to measure muscle CT attenuation of healthy
young and old dogs.
Methods: Healthy young (1–5 years old)
and old (>8 years old) pet Labrador Retrievers of optimal body weight
were eligible for the study. A CT was performed under mild sedation,
and the mean muscle attenuation of the left epaxial (paravertebral)
muscles over the 13th thoracic vertebral body was measured. To determine
the mean values, multiple freehand regions of interest were drawn on
the axial images and histogram analysis was performed.
Nine young dogs (5 female, 4 male; mean age = 2 ± 1 years) and 11 old
dogs (9 female, 2 male; mean age = 9 ± 1 years) were enrolled. Body
weight was not different between groups [mean weight for all
dogs = 30.7 ± 5.1 kg). Mean CT attenuation of the epaxial muscles was
significantly lower in old compared to young dogs (P = 0.005). There was a significant negative correlation between CT attenuation and age (r = −0.74, P < 0.001).
Qualitative and quantitative muscle changes occur in aging in both dogs
and humans. Additional studies evaluating functional muscle changes in
this canine model are warranted, as are studies to evaluate potential
benefits of exercise and nutritional modifications.
inpatient outcome of fragility fracture integrated rehabilitation
management between sarcopenic and non-sarcopenic patients after hip
Seung-Kyu Lim1, Sang Yoon Lee2, Jae Won Beom3 and Jae-Young Lim1
of Physical Medicine & Rehabilitation, Seoul National University
Bundang Hospital, Seoul National University College of Medicine,
Bundang, South Korea; 2Department of Physical
Medicine & Rehabilitation, Seoul Metropolitan Government Seoul
National University Boramae Medical Center, Seoul, South Korea; 3Department of Physical Medicine & Rehabilitation, Chung-Ang University College of Medicine, Seoul, South Korea
Hip fracture and sarcopenia are critical causes of mortality and loss
of function in elderly patients, and comprehensive rehabilitation is
important for preventing disability and maintaining health. This study
evaluates the effects of Fragility Fracture Integrated Rehabilitation
Management (FIRM) on functional outcome in sarcopenic and non-sarcopenic
patients in inpatient care following hip fracture surgery.
Patients over 65 years who underwent hip surgery for fragility hip
fracture at two university hospitals in Korea from July 2016 to May 2017
were entered the prospective study. After surgery, all patients
received FIRM of advanced physical, occupational therapy and education
for 2 weeks. The patients were divided into two groups according to the
presence of sarcopenia based on Asian Working Group for Sarcopenia
(AWGS) criteria. The demographic and functional characteristics were
analyzed before and after FIRM to evaluate the short-term outcome during
Results: Overall, 56 patients were
eligible for the study and patients satisfied the criteria of sarcopenia
were 18 (32.1%). There were no significant differences in premorbid
ambulatory status between the groups. Berg Balance Scale (BBS), Modified
Rivermead Mobility Index (MRMI) and Korean Instrumental Activities of
Daily Living were significantly different between the groups at
baseline. KOVAL, MRMI, BBS, Mini Mental State Examination and Modified
Barthel Index were significantly improved, and there were no differences
in the change between in the both groups after FIRM, but functional
ambulatory category was significantly more improved in non-sarcopenic
Conclusions: The functional level of hip fracture
patients with sarcopenia was lower than that of the patients those
without sarcopenia. FIRM may be effective for short-term functional
recovery in elderly patients who suffered fragility hip fracture with or
skeletal muscle mass index adjusted by height correlated more
practically with burn size in muscle wasting of post burn
Yoon Soo Cho, So Young Joo and Chong Hoon Seo
Department of Rehabilitation Medicine, Hallym University, College of Medicine, Seoul, South Korea
Severe burns are inevitably accompanied by a hypermetabolic and
hypercatabolic response. These result in a loss of skeletal muscle mass,
bone mineral mass and fat mass. Appropriate appendicular skeletal
muscle mass indices (ASMIs) is needed in burn patients for proper
nutritional intervention. This paper aims to compare diverse ASMIs and
to suggest more suitable index for burn survivors.
We conducted retrospective study with 162 burn patients. Appendicular
skeletal muscle mass (ASM) measured by dual-energy X-ray absorptiometry
was divided by height squared (kg/m2), weight (Wt)(%) and body mass
index (BMI) to obtain ASMIs. Sarcopenia was defined as the ASMI of 1 SD
below the sex-specific mean for young Korean adults.
The mean age of patients was 31.17 ± 5.08 years old. ASM loss was
dependent on the burn percentage of total body surface (β = −0.23, P = 0.001) with adjusting for age, sex, height (Ht), weight(Wt) and BMI. ASM/Ht2 in the group of ≥20% burn surface area (BSA) was significantly lower than in <20% BSA group (P = 0.005), while ASM/Wt(%) and ASM/BMI were not different between two groups (P = 0.14, P = 0.36).
Independent association between BSA and sarcopenia was showed in
multiple logistic regression analysis after adjustment for sex, age, Ht,
Wt and BMI in ≥10% BSA (adjusted ORs (AORs) = 1.23 [95% CI 0.42–3.57]),
≥20% BSA (AORs = 1.41 [0.53–3.76]) and ≥30% BSA group (AORs = 3.47
Conclusions: This study demonstrates ASM/Ht2
is related more closely to burn injury. The burn groups were at higher
risk for sarcopenia depending on the size of BSA, especially ≥30% BSA.
Handgrip strength and falls among community-dwelling older adults
Beatriz Fernandes1,3, Alejandro Mercant-Galán2,3 and Teresa Tomás1,3
1Escola Superior de Tecnologia da Saúde de Lisboa – Instituto Politécnico de Lisboa, Portugal; 2Universidad de Jáen; 32GHRG - Gerontology and Geriatric Health Research Group
Falls prevention in older adults includes early screening for fall
risk; risk factor assessment and specialized intervention. Several
variables such as balance, gait speed and mobility have been used to
assess the risk of falling. More recently, handgrip strength has also
been identified for this purpose. The aim of this study was to
investigate the relationship between handgrip strength and balance, gait
speed and mobility in community-dwelling older adults.
A sample of 45 community-dwelling older adults (16 M; 30F), aged
76.9 ± 8.6 was enrolled in the study. Inclusion criteria were age 65 and
over; ability to walk autonomously (with or without assistive devices)
and to understand and perform the tests. Participants were excluded if
they had limitations interfering with the performance of tests and
medical contraindications for exercise. Balance was assessed with the
Berg Balance Scale (BBS), mobility with the 8-foot-up-and-go-test, gait
speed with the 4 meter walk test and handgrip strength with the
hydraulic dynamometer Jamar®.
A Spearman's correlation was run to investigate whether there were associations between variables.
Results: A strong positive correlation was found between handgrip strength and balance (rs = 0.645, p = 0.000)
and handgrip strength and gait speed (rs = 0.593, p = 0.000). Results
from the 8-foot-up-and-go-test (7.8 ± 3.4 s) did not revealed increased
risk of falling; however, there was a strong negative correlation
between mobility and balance (rs = −0.758, p = 0.000), gait speed
(rs = −0.681, p = 0.000) and handgrip strength (rs = −0.632, p = 0.000).
For our participants as handgrip strength increases gait speed and
balance also increase. Decreases in balance, gait speed and handgrip
strength are related to mobility decline which is related to an
increased risk of falling. Our results point-out handgrip strength as a
valuable measure to identify the risk of falling. Further studies with
larger samples are needed to confirm these results.
risk of fall, fracture and rapid bone microstructure deterioration in
men with poor physical performance – the prospective STRAMBO study
Pawel Szulc, Philippe Wagner and Roland Chapurlat
INSERM UMR 1033, University of Lyon, Hôpital Edouard Herriot, Lyon, France
Introduction: Poor physical leg capacity is associated with poor bone microarchitecture (Blaizot, Osteopor Int, 2012)
and may increase the risk of fall and fracture. We assessed the
association of physical performance of lower limbs with subsequent
changes in distal tibia bone microarchitecture and the risk of fall and
fracture in older men.
Methods: A cohort of 817 men aged
60–87 was followed up prospectively for 8 yrs. At baseline, physical
performance was assessed using a score based on the clinical tests
(chair tests, standing with feet in side by side position with eyes open
or closed, 10-step tandem walk forward and backward). The score
accounted for the ability and time needed to perform each test (Szulc, JBMR, 2009).
Every year, men replied to questionnaires covering incident falls and
fractures. Distal tibia bone microarchitecture was assessed by
high-resolution pQCT (XtremeCT Scanco) at baseline and after 4 and
8 yrs. Statistical analyses were adjusted for relevant confounders.
Compared with men having good physical performance (best quartile), men
with poor performance had greater decrease in cortical thickness
(−2.05 ± 0.19 vs. −0.82 ± 0.11%/yr, p < 0.001) and cortical
density (−0.79 ± 0.06 vs. –0.42 ± 0.03%/year, p < 0.001). Poor
physical performance was associated with greater decrease in central
trabecular density and trabecular thickness (p < 0.001). Compared
with men having good physical performance, men with poor physical
performance had higher risk of recurrent falls (≥1 fall/year, n = 65, HR = 2.3, 95%CI: 1.1–5.1, p < 0.05) and of falls requiring hospitalization (n = 71, HR = 3.9, 95%CI: 1.7–9.0, p < 0.005). Men having poor physical performance had higher risk of non-spine fracture (n = 61, HR = 2.9, 95%CI: 1.2–7.1, p < 0.05).
In older home-dwelling men, poor physical performance of the lower
limbs was associated with greater decline in distal tibia bone
microarchitecture, higher risk of fall and higher risk of non-spine
Utility of phase angle as marker of low muscle mass, impaired muscle function and muscle quality in colorectal cancer patients
Nilian Carla Silva Souza1,2, Maria Cristina Gonzalez3, Renata Brum Martucci1,2, Viviane Dias Rodigues2, Nivaldo Barroso de Pinho2 and Carla Maria Avesani1
1Rio de Janeiro State University – Rio de Janeiro, Brazil; 2Brazilian National Cancer Institute – Rio de Janeiro, Brazil; 3Catholic University of Pelotas – Pelotas, Brazil
Cancer is a catabolic disease that leads to muscle loss, impaired
muscle function and quality and, ultimately, to sarcopenia. Phase angle
(PA) is a well-known marker of muscle mass, but its applicability as a
marker of impaired muscle function and muscle quality in oncologic
patients has not yet been investigated. Therefore, we aimed to
investigate the association between PA with measurements of skeletal
muscle mass, muscle function and muscle quality in colorectal cancer
Methods: This study included 194 colorectal
cancer patients (age: 60 ± 11 years; 58% men). The skeletal muscle mass
(SMM) and skeletal muscle attenuation were assessed by computed
tomography (CT) at the third lumbar vertebra. Muscle quality was
assessed by skeletal muscle gauge (SMG) obtained as SMM × skeletal
muscle attenuation, where high SMG indicates good muscle quality. Muscle
function was assessed by handgrip strength (HGS) and gait speed (GS).
The association between PA and the variables studied were assessed by
Spearman/Pearson's test. In order to investigate the association between
SMM, SMG, HGS and GS with PA, after adjustments for confounding
variables (sex, age and BMI), linear regression models were constructed.
Results: Most patients (62%) were overweight and obese (BMI ≥ 25 kg/m2). The PA was significantly associated with BMI (r = 0.36), with SMM (r = 0.66), SMG (r = 0.68), HGS (r = 0.53) and with GS (r = 0.32).
In the regression models, the PA remained as a significant and
independent predictor (p < 0.05) of SMM (r2 = 0.75), SMG (r2 = 0.70), HGS (r2 = 0.62) and GS (r2 = 0.16).
PA was independently associated with skeletal muscle mass, muscle
function and muscle quality in colorectal cancer patients. These results
suggest that PA is a marker muscle mass, function and quality in this
subset of patients.
Low muscle radiodensity is associated with pre-existing comorbidities in early stage colorectal cancer patients
Jingjie Xiao1, Bette J. Caan2, Erin Weltzien2, Elizabeth M. Cespedes Feliciano2, Candyce H. Kroenke2, Jeffrey A. Meyerhardt3, Vickie E. Baracos4, Marilyn L. Kwan2, Adrienne L. Castillo2 and Carla M. Prado1
Nutrition Research Unit, Department of Agricultural, Food and
Nutritional Sciences, University of Alberta, Edmonton, AB, Canada; 2Division of Research, Kaiser Permanente Northern California, Oakland, CA; 3Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; 4Department of Oncology, University of Alberta Cross Cancer Institute, Edmonton, AB, Canada
Comorbidities and computerized tomography (CT)-measured muscle
abnormalities are both common in cancer patients and evident in diseases
such as diabetes and obesity. This is the first study to examine the
association between comorbidities and muscle abnormalities in patients
with colorectal cancer (CRC).
Methods: This cross-sectional
study included 3051 patients with stage I-III CRC. Muscle abnormalities
were defined as low skeletal muscle mass index (SMI) or low skeletal
muscle radiodensity (SMD) quantified using diagnostic CT images.
Charlson comorbidities were ascertained. Chi-square tests were used to
compare the prevalence of comorbidities by the presence/absence of each
muscle abnormality. Logistic regression analyses were performed to
evaluate which comorbidities predicted muscle abnormalities adjusting
for age, sex, body mass index, weight change, stage, race/ethnicity, and
Results: Mean age was 63 years; 50% of patients
were male. The prevalence of low SMI and low SMD were 43.1% and 30.2%,
respectively. Comorbidities examined were more prevalent in patients
with low SMD than in those with normal SMD (58.6% vs. 34.4%, p < 0.001),
and most remained significant predictors of low SMD, including
myocardial infarction (odds ratio [OR] = 1.82, p = 0.017),
congestive heart failure (OR = 3.34, p < 0.001), peripheral vascular
disease (OR = 2.20, p < 0.001), diabetes with or without
complications (OR = 1.61, p = 0.008; OR = 1.47, p = 0.003,
respectively) and renal disease (OR = 2.23, p < 0.001). No
comorbidities were associated with low SMI except for diabetes with
complication which was associated with a lower likelihood of low SMI
(OR = 0.64, p = 0.007).
Conclusions: Prevalence of
muscle abnormalities was high in early stage CRC. Pre-existing
comorbidities were most commonly associated with low SMD, suggestive of a
potential shared mechanism between fat infiltration into muscle and
each of these comorbidities.
between cachexia, patient-generated Subjective Global Assessment and
hand grip strength in patients with advanced cancer in palliative care
unit in Brazil
Nathália Masiero Cavalcanti de Albuquerque1,2, Juliana Rodrigues1, Emanuelly Varea Maria Wiegert1, Larissa Calixto-Lima1, Livia Costa de Oliveira1, Mayane Marinho Esteves Pereira1 and Wilza Arantes Ferreira Peres2
1Palliative Care Unit, National Cancer Institute José Alencar Gomes da Silva (INCA), Rio de Janeiro, RJ, Brazil; 2Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
is frequently observed in advanced cancer patients, and it is
associated with muscle mass loss and maybe strength. Therefore, we aimed
to correlate cancer cachexia with Subjective Global Assessment Short
Form (PG-SGA SF) and hand grip strength (HGS) in patients with
palliative care. This is an observational study comprising 525 patients
attended for the first time, presenting different locations of tumor.
Cachexia was defined by Fearon et al. (2011) criteria: 1) weight loss >2% in 6 months (A) + body mass index (BMI) <20 kg/m2; or 2) A + Mid-upper arm muscle area (low muscle mass) <32 cm2 for male and <18 cm2
for female. Low muscle strength was characterized by HGS <20 kg for
female and <30 kg for male. Associations between clinical and
nutritional parameters with cachexia were tested by univariate and
Patients presented a median age of 63 (54;72, IQR) years, 57.5% were female. Half of then presented Karnofsky Performance Status
(KPS) < 50% and 60% had albumin <3.5 g/dl and CRP ≥10 mg/dl. Low
BMI and cachexia was observed in 37% and 61% of the patients,
respectively. Reduced HGS in 79% of women and 74% of men. Patients with
cachexia had worst nutritional status by PG-SGA SF and lower HGS
compared with those without (Figure 1).
In the univariate regression gastrintestinal tract tumor, CRP and KPS
<50%, albumin (<3.5 g/dL), HGS and PG-SGA SF (≥9) presented an
elevated Odds Ratio (OR) for cachexia (p < 0.02). In the
multivariate analysis PG-SGA (≥9) presented the highest OR (2.43 [CI
95%: 1.52; 3.90]) against gender, GI tract tumor, and HGS. In
conclusion, nutritional risk by PG-SGA SF, low muscle strength and GI
tract tumor, but not KPS were associated with an increased odds to
of abridged Patient-Generated Subjective Global Assessment (aPG-SGA)
and Handgrip Strength compared to cancer cachexia in patients treated at
a Palliative Care Unit in the city of Rio de Janeiro- Brazil (n = 525).
of sarcopenia and survival with different diagnostic methods in
patients with advanced cancer in Palliative Care Unit in Brazil
Nathália Masiero Cavalcanti de Albuquerque1,2, Juliana Rodrigues1, Emanuelly Varea Maria Wiegert1, Larissa Calixto-Lima1, Livia Costa de Oliveira1, Mariana dos Santos Campelo Queiroz1 and Wilza Arantes Ferreira Peres2
1Palliative Care Unit, National Cancer Institute José Alencar Gomes da Silva (INCA), Rio de Janeiro, RJ, Brazil; 2Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
has been evaluated by different methods in patients with advanced
cancer. Thus, the objective of this study is to describe the association
of sarcopenia with survival by different methods in patients with
advanced cancer in palliative care.
This is an observational and
prospective study including 342 patients [age: 63 (55; 72, IQR) years;
55.8% female; 65.5% with KPS ≥50%].
Survival time was established by the time of inclusion until 90 days of
follow-up. Sarcopenia was define by patients with reduced muscle mass
and strength, where low muscle mass: 1) Mid-upper arm muscle area
(MUAMA) <32 cm2 for male and <18 cm2 for
female; 2) Calf circumference (CC) < 31 cm for both genders; and 3)
Appendicular skeletal muscle mass (ASM) described by Baumgartner (1998)
<7.26 kg/m2 for male and <5.45 kg/m2 for
female. Low muscle strength was defined by hand grip strength (HGS)
<30 kg for male and <20 kg for female. Kaplan–Meier was used to
calculate survival and Log-rank test to evaluate differences between
then. The association between sarcopenia and survival was evaluated by
hazard ratio (HR) and 95% confidence interval (CI) in a crude univariate
analysis and multivariate COX regression adjusted for co-founders,
including parameters with p-value <0.02 in the previous analysis.
of sarcopenia was 86%, 32.2% and 36.8%, for ASM, MUAMA and CC,
respectively. Patients with sarcopenia showed shorter survival for those
for all three methods. In the univariate analysis, patients with
sarcopenia had a significant worse survival for ASM (HR [95%CI]: 1.78
[1.29; 2.46]), MUAMA (1.92 [1.42; 2.60]) and CC (1.89 [1.41; 2.53]). In
the Multivariate analysis, MUAMA (1.55 [1.11; 2.15]) and CC (1.50 [1.08;
2.07]) remained significant. In conclusion, our data suggest that
patients with sarcopenia have reduced survival, especially, when MUAMA
and was used as criteria method.
Grip strength as an important part of the diagnostic criteria for sarcopenia in advanced cancer
Guro Brigitte Stene1,3, Trude R. Balstad2,3, Barry J.A. Laird2,4, Neil Jones7, Asta Bye5,6, Kenneth Fearon7, Stein Kaasa2,3 and Tora S. Solheim2,3
of Neuromedicine and movement science, Faculty of Medicine, Norwegian
University of Science and Technology (NTNU), Olav Kyrres gt. 10,
Trondheim, N-7491, Norway; 2European Palliative Care
Research Centre (PRC), Department of Cancer Research and Molecular
Medicine, Faculty of Medicine, Norwegian University of Science and
Technology (NTNU), Olav Kyrres gt. 10, Trondheim, N-7491, Norway; 3Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Olav Kyrres gt. 10, Trondheim, N-7491, Norway; 4Edinburgh Cancer Research Centre, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XR, UK; 5Regional Advisory Unit for Palliative Care, Department of Oncology, Oslo University Hospital, Oslo, Norway; 6Department
of Nursing and Health Promotion, Faculty of Health Sciences, Oslo and
Akershus University College of Applied Sciences, Oslo, Norway; 7Department of Surgery, School of Clinical Sciences, University of Edinburgh, Little France Crescent, Edinburgh, EH16 4SA, UK
Patients with advanced cancer are at risk of developing sarcopenia that
can impede a positive outcome of chemotherapy treatment. In relation to
aging, classification of sarcopenia should include assessment of both
muscle mass and muscle strength; however, in cancer, classification is
usually based on assessment of muscle mass alone. The addition of muscle
strength assessment to classify sarcopenia also in cancer patients
could improve precision of diagnosis and better predict clinical
outcomes. This study aims to determine prevalence of sarcopenia and
examine the association between low skeletal muscle mass and grip
strength in patients with advanced cancer.
Methods: This is
a cross sectional study based on data collected from patients newly
diagnosed with advanced stage lung and pancreatic cancer starting
chemotherapy. Muscle mass was measured from CT-images as cross sectional
area (cm2) of the sum of skeletal muscles at the third lumbar vertebral level. Skeletal muscle index, SMI (cm2/height, m2) was calculated and cut-offs used were <52.4 cm2/m2 for men; <38.2 cm2/m2
for women. Grip strength (kg) was assessed by a handheld dynamometer
using the mean value of three test trials and cut-offs were <40 kg
for men and <30 kg for women.
Results: The sample
consisted of 45 patients (26 men; 19 women) aged 35–76 years (mean
60 years) with a performance score (Karnofsky) of 80 (range 70–100). SMI
(mean 45.5 ± 8.2 cm2/m2) was strongly correlated to low grip strength in this population (r = 0.567; p < 0.01).
The prevalence of sarcopenia based on SMI alone was 60%. When grip
strength was used in combination with SMI to diagnose sarcopenia, the
prevalence was 31%.
Conclusions: Assessment of grip
strength is a simple tool that could be considered an important part of
the classification of sarcopenia in patients with advanced cancer.
Further studies are warranted to determine cut-offs for grip strength
associated with important clinical outcomes in advanced cancer.
impact of changes in skeletal muscle mass (SMM) on changes in quality
of life (QoL) in metastatic colorectal cancer (mCRC) patients
Jeroen W.G. Derksen1, Sophie A. Kurk1, Petra H.M. Peeters1, Bram Dorresteijn2, Marion Jourdan2, Cornelis J.A. Punt3, Miriam Koopman1 and Anne M. May1
1University Medical Center Utrecht, Utrecht, The Netherlands; 2Nutricia Research, Utrecht, The Netherlands; 3Academic Medical Center, Amsterdam, The Netherlands
Increasing evidence indicates that low SMM is associated with poor
outcomes in various cancers, including mCRC. We recently showed, using
data of the randomized phase III CAIRO3 study (Lancet, 2015), that
skeletal muscle loss was associated with poor survival during first line
maintenance treatment with capecitabine + bevacizumab (CAP-B) or
observation (ASCO, 2017), after induction treatment with
capecitabine + oxaliplatin + bevacizumab. The impact of SMM change on
QoL is not yet known. Here, we investigate the association between
change of SMM and concomitant QoL changes in mCRC patients.
Patients were followed during CAP-B or observation until first
progression of disease (PD1). Routine CT scans were analyzed for SMM
(from skeletal muscle cross-sectional area at L3). Change in SMM was
measured continuously and categorized into loss (>2%), stable (≤2%
loss- ≤ 2% gain), and gain (>2%). Multiple linear regression models
were applied to study the association between change in SMM and
concomitant change in QoL (EORTC-QLQ-C30v.3), adjusted for relevant
Results: 221 patients were included (64% male,
mean age 63.5 ± 8.4 years). 24% lost, 27% maintained, and 49% gained
SMM, while on average patients gained 0.5 ± 1.7 kg SMM. Mean QoL at
randomization and PD1 was 74.7 ± 18.4 and 74.3 ± 16.8, respectively. One
kilogram SMM increase was significantly associated with 2.7 points
increase (95%CI:1.1;4.4) in QoL. Compared to patients who lost SMM,
maintaining or gaining SMM was associated with clinically relevant
increase of QoL (9.9 (CI:2.4;17.5) and 14.7 (CI:8.0;21.4),
respectively), and role functioning (12.0 (CI:2.2; 21.7) and 17.9
(CI:9.4;26.5)), reduced fatigue (−10.0 (CI: –17.4; –2.5) and −15.0 (CI:
–21.6; –8.5)), pain (−7.4 (CI: –16.7;2.0) and −16.3 (CI: –24.6; –8.1)),
and appetite loss (−12.3 (CI: –22.2; –2.5) and −17.9 (CI: –26.5; –9.2)).
Stable SMM during first line CAP-B treatment or observation was
consistently associated with several clinically relevant increased QoL
aspects. In addition, SMM gain was significantly associated with
substantially larger positive QoL changes, underlining the importance of
SMM in mCRC.
detection of skeletal muscle atrophy using a multiple plasma-free amino
acid index in patients with advanced pancreatic cancer
Shuichi Mitsunaga1,2, Michihiro Takada3, Sachiko Nishikawa3, Akira Imaizumi3, Makoto Ishii3, N. Tatematsu4, Masafumi Ikeda1 and Atsushi Ochiai2
1Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 2Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Japan; 3Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Japan; 4Department of Rehabilitation, National Cancer Center Hospital East, Kashiwa, Japan
Loss of skeletal muscle mass (SMM) is a feature of both aging and
cancer cachexia and can influence plasma free amino acid (PFAA) levels
via metabolic abnormalities. The early detection of SMM loss using a
multivariate index composed of PFAAs might be useful for managing
patients with advanced pancreatic cancer (PCa).
Patients with treatment-naïve advanced PCa were enrolled. The whole body
skeletal muscle index (wSMI) and cachexia were measured using
bioelectrical impedance analysis and the diagnostic criteria for
cachexia of the European Palliative Care Research Collaborative at
baseline and one month later. Each patient was assigned to an atrophy or
a non-atrophy group based on the change in wSMI after one month. The
concentrations of 19 PFAAs were measured using liquid
chromatography–mass spectrometry. An index consisting of the PFAAs at
baseline was evaluated for its ability to discriminate atrophy one month
later in both younger (<70 years) and older groups.
Atrophy was observed in 49% of the 161 PCa patients. The independent
risk factors for atrophy were an advanced age (odd ratio [OR]: 2.1, P = 0.04) and cachexia at one month (OR: 4.0, P < 0.01).
The areas under the curves (AUCs) based on a receiver operating
characteristic (ROC) curve analysis of the PFAA index for discriminating
atrophy from non-atrophy were calculated using single or multiple
PFAAs. The single PFAA analyses revealed that aging affected the
diagnostic ability of some PFAAs. The best AUCs for the multiple PFAA
indices were 0.85 (95% confidence interval [CI], 0.74–0.96) for the
older group and 0.67 (95% CI, 0.56–0.77) for the younger group.
Conclusions: SMM atrophy was related to aging and cachexia in patients with advanced.
Muscle radiodensity is indicative of triglyceride content in skeletal muscle of cancer patients
Amritpal S. Bhullar1, Ana Anoveros-Barrera1, Abha Dunichand-Hoedl1, Karen Martins1, David Bigam2, Todd McMullen2, Charles T. Putman3,4, Vickie Baracos5 and Vera Mazurak1
of Agricultural, Food & Nutritional Science, Faculty of Agriculture
Life and Environmental Sciences, University of Alberta, Edmonton, AB,
Canada; 2Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 3Faculty of Physical Education and Recreation, University of Alberta, Edmonton, AB, Canada; 4Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada; 5Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
Computed Tomography (CT) cross-sectional imaging has been recently
applied to evaluate muscle area and radiodensity in cancer patients.
Studies of muscle radiodensity, reported in Hounsfield Units (HU), reveals an association with poor survival in a variety of cancer types.[2-5] In healthy adults, muscle radiodensity inversely associates with triglyceride content
but no studies to date have reported this association in cancer
patients. It is also not known whether lipid is located inside myocytes
as lipid droplets or adjacent to the myocytes within adipocytes.
Rectus abdominis (RA) muscle biopsies were collected during surgery
from patients diagnosed with gastrointestinal cancers. Skeletal muscle
radiodensity was assessed by analyzing CT images at the 3rd lumbar
vertebra, as well as RA specifically. Triglyceride content of muscle was
analysed quantitatively using gas chromatography. RA muscles, frozen
for histology, were stained for neutral lipid content using Oil Red O
(ORO) to determine location of neutral lipids. Percent area of pixels
with ORO stain was calculated by Volocity6.3 Software.
Results: Mean muscle radiodensity and RA radiodensity were inversely associated with triglyceride content (μg/mg) (r = −0.518, p = 0.023 and r = −0.481, p = 0.032,
respectively). Of the total percent area of neutral lipid, mean percent
area present outside myocytes was 54% compared to 46% mean percent area
inside myocytes. There was no significant difference in percent area of
neutral lipids present inside (42% vs 54%, p = 0.309)
and outside (58% vs 46%, p = 0.309) myocytes in muscle with
low versus high triglyceride content, respectively.
In cancer patients, overall abdominal muscle and rectus abdominis
radiodensity is associated with triglyceride content of the muscle
indicating that low muscle radiodensity is indicative of fatty
infiltration, which appears to occur equally inside and outside of the
myocyte. Future studies will enable us to understand effects of high
triglyceride content within muscle of cancer patients.
- 1Measurement of skeletal muscle radiation attenuation and basis of its biological variation. Acta Physiol (Oxf). Mar 2014;210(3):489–497., , , et al.
- 2Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Apr 20 2013;31(12):1539–1547., , , et al.
muscle attenuation is a prognostic factor for survival in metastatic
breast cancer patients treated with first line palliative chemotherapy. Breast (Edinburgh, Scotland). Feb 2017;31:9–15., , , , , .
skeletal muscle radiation attenuation and visceral adiposity are
associated with overall survival and surgical site infections in
patients with pancreatic cancer. J Cachexia Sarcopenia Muscle. 10/2602/22/received08/26/revised09/05/accepted 2017;8(2):317–326., , , et al.
- 5Skeletal muscle quality is associated with worse survival after pancreatoduodenectomy for periampullary, nonpancreatic cancer. Ann Surg Oncol. 09/0804/06/received 2017;24(1):272–280., , , et al.
- 6Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content. Journal of applied physiology (Bethesda, Md: 1985). Jul 2000;89(1):104–110., , , , .
of advanced pancreatic cancer patients showing a decrease of the
skeletal muscle mass while receiving first-line chemotherapy
Noriatsu Tatematsu1, Syuichi Mitsunaga2,3, Masafumi Ikeda2 and Atsushi Ochiai3
1Department of Rehabilitation, National Cancer Center Hospital East, Kashiwa, Japan; 2Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 3Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Japan
Loss of skeletal muscle mass (SMM) represents a clinical feature of
cancer cachexia. The goal of this study was to identify the factors
associated with the loss of SMM in advanced pancreatic cancer (PCa)
patients receiving first-line chemotherapy.
Advanced PCa patients who were scheduled to receive first-line
chemotherapy were eligible. The SMM was measured using the 3rd lumbar
vertebral skeletal muscle index (L3-SMI). Activity, symptoms, and
quality of life (QOL) were prospectively evaluated at baseline and one
month after the start of chemotherapy using Karnofsky Performance Status
(KPS) and questionnaire (Japanese version of the M.D. Anderson Symptom
Inventory). Each patient was assigned to atrophy or non-atrophy group on
the basis of the change of the L3-SMI over one month. The differences
in the assessment results between the two groups were examined at
baseline and one month after the start of treatment. Landmark analysis
was used for analysis of the overall survival (OS).
Results: The data of 159 patients (age in mean: 65.3 years, KPS in mean: 88.7, mean body mass index: 21.7 kg/m2, mean L3-SMI: 41.8 cm2/m2) were evaluated. There were no differences in the baseline characteristics between the atrophy group (n = 78, change of L3-SMI in mean: −3.2 cm2/m2) and non-atrophy group (n = 81, +0.7 cm2/m2). At 1 month, the KPS score was lower in the atrophy group than in the non-atrophy group (83.4 vs. 89.3, P < 0.01). QOL score in atrophy group were worsen to be compared with those in non-atrophy group (3.3 vs. 2.3, P = 0.04).
Survival analysis revealed that atrophy group showed poor OS, compared
to non-atrophy group (5.9 vs. 11.9 mo, P < 0.01).
Loss of skeletal muscle mass occurring during first-line chemotherapy
is related to the deterioration of activity, QOL and poor OS in advanced
Analysis of body composition by bioimpedance in breast cancer patients at first diagnosis
Alessio Molfino1, Maria Ida Amabile1,2, Cesarina Ramaccini1, Alessandro De Luca2, Federica Maceli2, Massimo Monti2, Filippo Rossi Fanelli1 and Maurizio Muscaritoli1
1Department of Clinical Medicine, Sapienza - University of Rome, Rome, Italy; 2Department of Surgical Sciences, Sapienza - University of Rome, Rome, Italy
Obesity represents a major under-recognized preventable risk factor for
cancer development and recurrence, including breast cancer (BC).
Obesity is highly prevalent in western countries, and it contributes to
almost 50% of BC in older women. However, although high body mass index
(BMI) may indicate overweight and obesity, often low muscle mass may be
present at BC diagnosis, impacting negatively on outcomes.
aimed at assessing body composition in BC patients at the moment of
cancer diagnosis and the association between body composition and
Methods: BC patients were enrolled
before undergoing breast surgery and any other therapy. Clinical
characteristics were collected, including BMI (weight/height2),
waist circumference (cm), while muscle mass (MM) (kg) and adiposity
(kg) were assessed by bioelectrical impedance analysis (InBody 770®, InBody Co, Ltd., kindly provided by Caresmed, Italy). Skeletal muscle index (SMI) was calculated as MM/height (m)2. Parametric and non-parametric tests were performed, as appropriate.
A total of 19 consecutive BC patients were studied. Age (years) was
54.4 ± 11.2. BMI was 25.2 ± 3.8 and MM was 23.3 ± 3.2. Based on SMI
cut-off values for sarcopenia, we did not find this condition in all
patients (9.1 ± 1.2). Eleven patients reported involuntary body weight
loss (between 3 and 6 kilograms) in the previous 6 months, whose BMI
tended to be lower (23.6 ± 2.4) although not significantly different
with respect to the patients without body weight loss (26.3 ± 4.3) (P = 0.07).
Patients reporting body weight loss had a MM significantly lower with
respect to patients without body weight loss (P = 0.04) and a lower
phase angle value (P = 0.01), as well as lower SMI (P = 0.02).
Besides the clinical importance of the anthropometric values, body
composition analyses revealed at the moment of BC diagnosis lower
muscularity in patients presenting involuntary body weight loss in the
previous months. These preliminary results suggest that body composition
analysis should be included in the evaluation of nutritional status,
since BMI and weight loss cannot discriminate the subtle changes
occurring in body compartments in early phases of disease.
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of low skeletal muscle mass and density on short and long-term outcome
after resection of stage I-III colorectal cancer: results from a
prospective multicenter observational cohort study
Jeroen L.A. van Vugt1, Robert R.J. Coebergh van den Braak1, Zarina S. Lalmahomed1, Wietske W. Vrijland2, Jan W.T. Dekker3, David D.E. Zimmerman4, Wouter J. Vles5, Peter P.L.O. Coene6 and Jan N.M. IJzermans1
1Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands; 2Department of Surgery, Sint Franciscus – Vlietland Hospital, Rotterdam, the Netherlands; 3Department of Surgery, Reinier de Graaf Hospital, Delft, the Netherlands; 4Department of Surgery, Elisabeth-Twee Steden Hospital, Tilburg, the Netherlands; 5Department of Surgery, Ikazia Hospital, Rotterdam, the Netherlands; 6Department of Surgery, Maasstad Hospital, Rotterdam, the Netherlands
Preoperative low skeletal muscle mass and density are associated with
increased postoperative morbidity in patients undergoing curative
colorectal cancer surgery. However, the long-term effects of low
skeletal muscle mass and density remain uncertain.
Patients with stage I–III colorectal cancer undergoing surgery,
enrolled in a prospective observational cohort study, were included.
Skeletal muscle mass and density were measured on CT. Patients with high
and low skeletal muscle mass and density were compared regarding
postoperative complications and mortality, disease-free survival (DFS),
overall survival (OS), and cancer-specific survival (CSS).
In total, 816 patients (53.9% men, median age 70) were included; 50.4%
had low skeletal muscle mass and 64.1% low density. The severe
postoperative complication rate was significantly higher in patients
with low versus high skeletal muscle and density (20.9% versus 13.6%, p = 0.006; 20.0% versus 11.8%, p = 0.003).
Low skeletal muscle density was independently associated with severe
postoperative complications (OR 1.89, 95%CI 1.11–3.23, p = 0.020).
Ninety-day mortality was higher in patients with low skeletal muscle
mass and density compared with patients with high skeletal muscle mass
and density (3.6% versus 1.7%, p = 0.091; 3.4% versus 1.0%, p = 0.038).
No differences in DFS were observed. After adjustment for covariates
such as age and comorbidity, univariate differences in OS and CSS
Conclusions: Low skeletal muscle mass and
density are associated with short-term, but not long-term, outcome in
patients undergoing colorectal cancer surgery. These findings recommend
putting more emphasis on preoperative management of patients at risk for
surgical complications, but do not support benefit for long-term
Correlations of serum creatinine with functional capacity and survival in patients with glioblastoma
Wenli Liu, Aiham Qdaisat, Jason Yeung, Gabriel Lopez, Jeffrey S. Weinberg, Lorenzo Cohen, Eduardo Bruera and Sai-Ching J. Yeung
The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Creatinine is exclusively produced by striated muscle which makes it a
reliable surrogate of skeletal muscle mass under stable conditions.
Studies reported that low serum creatinine was associated with increased
morbidity and mortality across different race, age, and disease groups.
We examined the correlations between serum creatinine and physical
function as well as serum creatinine and survival in patients with
Methods: 404 consecutive glioblastoma
patients who received tumor resection between 1/1/2010 and 12/31/2014
were reviewed. Data about treatments (extent of tumor resection,
radiation therapy, and use of temozolamide), medical history, vital
signs, weight, height, Karnofsky Performance Status (KPS), and lab tests
were collected. Charlson Comorbidity Index (CCI) was calculated with
ICD-9 codes. Bivariate associations between baseline KPS and serum
creatinine, and body mass index (BMI) were analyzed using Pearson
correlation coefficients. Cox regression for survival analysis was
Results: The mean age of the population was 58
(+13) years. 64% were male. Death rate was 78%. The correlation
coefficients for KPS and creatinine 0.15 (P = 0.003), for KPS and BMI 0.08 (P = 0.103).
Patients with low serum creatinine (<0.6 mg/dL in female,
<0.7 mg/dL in male) had shorter survival (HR = 1.65 [95%
CI = 1.07–2.55], P = 0.023)
when adjusted for known survival predictors including age, extent of
tumor resection, and treatment strategies.
Serum creatinine positively correlates with functional performance
status. Low serum creatinine predicts mortality in patients with
glioblastoma. The unique utility of creatinine as a marker of muscle
mass deserves more research and clinical attention.
Identification of immune cells in the muscle of cancer patients
Ana Anoveros-Barrera1, Amritpal S. Bhullar1, Abha Dunichand-Hoedl1, Karen Martins1, David Bigam2, Vickie Baracos3 and Vera Mazurak1
of Agricultural, Food & Nutritional Science, Faculty of Agriculture
Life and Environmental Sciences, University of Alberta, Edmonton, AB,
Canada; 2Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 3Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
Background: Inflammation is a recognized contributor to muscle wasting.
Gene array analysis in human biopsies has revealed that immune cell
recruitment is a major event occurring in cancer patients experiencing
systemic inflammation. Lymphoid and myeloid cells in the tissue influence muscle atrophy through diverse mechanisms[3, 4];
however, little is known about the muscle's immunological environment
and its relationship to muscle loss in conditions of malignancy.
Therefore, we hypothesized that features of muscle atrophy are related
to a higher recruitment of immune cells in the muscle of patients with
Methods: Rectus abdominis biopsies and computed tomography (CT) images were collected from cancer patients (n = 22)
at the University of Alberta Hospital, Edmonton, Canada, from July 2015
to August 2016. Frozen muscle biopsies cut in transverse sections were
stained with immunofluorescence to evaluate immune cells: T cells (CD8+
and CD4+), antigen presenting cells (APCs; CD3-CD4+), and granulocytes
(CD11b+). Features of muscle atrophy were explored by evaluating
histopathological components such as mean muscle fiber area (μm2) and computed CT images to obtain muscle cross sectional area (CSA; cm2). Spearman's coefficient was used to assess correlations.
Results: Muscle with higher CSA (cm2) (r = 0.66, P = 0.001) and mean fiber area (μm2) (r = 0.55, P = 0.008)
had a larger number of T cells (CD4+ and CD8+ combined). CD8+ T cells
(not CD4+ T cells) maintain a significant association with muscle CSA (r = 0.53, P = 0.012) and mean muscle fiber area (r = 0.49, P = 0.021).
APCs and granulocytes were not related to any muscle feature evaluated;
however, APCs were positively correlated to number of CD8+ T cells (r = 0.45, P = 0.036).
Lymphoid and myeloid cells are present in the muscle of cancer
patients. In particular, T cells seem to be associated with better
muscle condition. Results suggest interaction between CD8+ T cells and
APCs. Further exploration will enable understanding the influence of
immune cells within the muscle of cancer patients.
muscularity and myosteatosis is related to the host systemic
inflammatory response in patients undergoing surgery for colorectal
cancer. 2015;0(0). doi:10.1097/SLA.0000000000001113., , , .
session presentation: systemic inflammation is associated with
concurrent inflammatory gene expression in skeletal muscle of advanced
cancer patients. 3rd Cancer Cachexia Conference, Washington DC. September 2016, , et al.
- 3Coculture with autologous myotubes of cytotoxic T cells isolated from muscle in inflammatory myopathm. 1991., .
- 4Regulation of muscle growth and regeneration by the immune system. Nat Rev Immunol 2017;17(3):165–178. doi:https://doi.org/10.1038/nri.2016.150..
CT-assessed muscle abnormalities are associated with poor prognosis post colon cancer resection surgery
Jingjie Xiao1, Bette J. Caan2, Peter D. Peng3, Erin Weltzien2, Elizabeth M. Cespedes Feliciano2, Candyce H. Kroenke2, Jeffrey A. Meyerhardt4, Vickie E. Baracos5, Marilyn L. Kwan2, Adrienne L. Castillo2 and Carla M. Prado1
Nutrition Research Unit, Department of Agricultural, Food and
Nutritional Sciences, University of Alberta, Edmonton, AB, Canada; 2Division of Research, Kaiser Permanente Northern California, Oakland, CA; 3Medical Center and Redwood City Medical Center, Kaiser Permanente Northern California, Oakland, CA; 4Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; 5Department of Oncology, University of Alberta Cross Cancer Institute, Edmonton, AB, Canada
Despite advanced operative techniques for resection surgery, a large
number of patients with colon cancer still suffer from post-operative
morbidity. This leads to delayed subsequent therapy, prolonged hospital
stay, and potentially worse prognosis. Computerized tomography
(CT)-measured muscle abnormalities are of emerging interest to surgeons
due to their potential value for post-operative risk stratification.
This study investigated the independent prognostic effects of muscle
abnormalities on surgical outcomes.
Methods: Patients diagnosed with stages I–III colon cancer from 2006 to 2011 were included (n = 1,715).
Muscle abnormalities were defined as a low skeletal muscle index (SMI)
and/or radiodensity (SMD) measured on pre-operative CT images.
Differences in demographic, clinical and surgical outcomes were compared
by each muscle abnormality using independent t-tests or
Chi-squared tests. Logistic regression was used to evaluate the
associations of muscle abnormalities with post-surgical length of
hospitalization, any complication(s) and readmission up to 30 days
post-surgery or post-discharge. Cox proportional hazards regression was
performed to examine the effect of muscle abnormalities on 30-day
Results: Mean age was 64.0 ± 11.2 years and
55.5% were female. Patients with low SMI (OR = 1.37, 95% CI 1.10–1.72)
or low SMD (OR = 1.50, 95% CI 1.15–1.96) were more likely to remain
hospitalized ≥7 days after surgery, and had higher risk of 30-day
mortality (low SMI: HR = 4.65, 95% CI 1.43–15.06; low SMD: HR = 3.34,
95% CI 1.08–10.30). Additionally, patients with low SMI were more likely
to have at least one post-surgical complication (OR = 1.26, 95% CI
1.02–1.55). Readmission rate was not associated with any muscle
Conclusions: Muscle abnormalities were
associated with poorer surgical outcomes, including longer
hospitalization and a higher risk of short-term mortality. Low SMI was
associated with a higher risk of post-surgical complications. Research
should evaluate whether targeting potentially modifiable factors
preoperatively, such as increasing muscle mass and/or radiodensity may
improve post-operative outcomes.
of sarcopenia on dose limiting toxicities (DLT) in metastatic
colorectal cancer (mCRC) patients receiving palliative systemic
Sophie Kurk1,2, Petra Peeters2, Jeroen Derksen1,2, Rebecca Stellato2, Bram Dorresteijn3, Marion Jourdan3, Cornelis Punt4, Miriam Koopman1 and Anne May2
1University Medical Center Utrecht, Utrecht, The Netherlands; 2Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; 3Nutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, The Netherlands; 4Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Increasing evidence suggests that severe skeletal muscle (SM) loss
(sarcopenia) is associated with reduced overall survival (OS) in mCRC.
We recently found that, using data of the randomized phase 3 CAIRO3
study (Lancet, 2015), SM loss was related to shorter OS during
first-line maintenance treatment with capecitabine + bevacizumab or
observation. Subsequently, sarcopenia at start of more intensive
reinduction treatment with oxaliplatin + capecitabine + bevacizumab
(CAPOX-B) was associated with shorter time to progression and OS (ASCO, 2017).
As a potential risk factor for reduced survival we explored whether
sarcopenia was associated with DLT during CAPOX-B reinduction treatment.
CAIRO3 patients were included who received CAPOX-B reinduction
treatment. DLT were defined as any dose delay/reduction/discontinuation
of systemic treatment because of reported CTCAE(v3.0) toxicities at
start or during treatment. Poisson regression models, adjusted for
confounders, were used to study the association between sarcopenia and
Results: 254 patients received CAPOX-B reinduction
treatment. 39% of patients were sarcopenic and compared to normal SM
patients we found no statistically significant differences in age and
sex (sarcopenic vs normal SM: mean age 63.6 ± 9.1 vs 61.9 ± 8.5 years, p = .20 and 39% vs 31% women, p = .31).
BMI was significantly lower in sarcopenic patients, but patients were
on average still overweight (25.9 ± 3.8 vs 27.2 ± 3.8 p = .01).
Overall, 67% experienced ≥1 DLT. At start of CAPOX-B, 25% already
received a dose reduction and the risk of dose reduction at start was
significantly higher for sarcopenic patients compared to normal SM (RR
1.8 (CI:1.08–2.90)). Despite more frequent dose reductions at start,
sarcopenic patients did not have a significantly lower risk of DLT
during CAPOX-B (RR sarcopenia vs normal SM 0.86 (CI: 0.46–1.45)).
Sarcopenia was significantly associated with dose reductions at start
of CAPOX-B reinduction treatment, and not with DLT during CAPOX-B
reinduction treatment. Possible explanations for dose reductions at
start might be more frequent toxicities during previous treatment
wasting in hemodialysis and lung cancer patients is mediated through
down and up-regulation of several proteins common to both diseases,
including actors of the proteasome and the autophagy proteolytic systems
Julien Aniort1,2, Cécile Polge1, Agnes Claustre1, Lydie Combaret1, Daniel Béchet1, Didier Attaix1, Anne-Elisabeth Heng1,2 and Daniel Taillandier1
1Institut National de la Recherche Agronomique, UMR 1019, Human Nutrition Unit (UNH), 63122, St Genès Champanelle, France; 2Service
de Néphrologie Réanimation Médicale, Pôle Respiratoire,
Endocrinologie-Diabétologie, Urologie, Néphrologie-Dialyse, Nutrition
Clinique, Infectiologie, Réanimation Médicale, Hygiène Hospitalière
(REUNNIRH), 63000, Clermont-Ferrand, France
Muscle atrophy is frequently encountered in diseased patients. It
contributes to patient's frailty and is associated with an increased
risk of death. Studies using animal models suggest the involvement of
the Ubiquitin Proteasome System (UPS) in renal failure-induced muscle
atrophy. However, this remains to be established in humans. Another
important goal is to detect markers that may help fighting against
muscle atrophy through nutritional or pharmacological strategies.
Indeed, it is very difficult to counteract the increased proteolysis
when it is established. Our objectives were (i) to identify the
proteolytic systems activated in chronic hemodialysis (HD) or lung
cancer (LC) patients, i.e. pathologies having a different etiology and
(ii) to identify markers specific to the activation of muscle atrophy
processes independently of the pathology per se.
Methods: Muscle biopsies (n = 7
per group) were obtained upon programmed surgery. mRNA and protein
levels were determined using qRT-PCR, immunoblotting and proteomic
Results: We found that the UPS and autophagy
were activated in both HD and LC patients. Mass spectrometry analysis
identified >1700 proteins. Main component analysis revealed 3
distinct protein expression profiles corresponding to the 3 groups
studied. We identified 106 proteins that were significantly modified
(decreased or increased) in both HD and LC patients compared to controls
(CT). Hierarchical cluster analysis showed that expression levels of
these proteins distinguished diseased (HD or LC) vs. CT patients.
Orthogonal partial least square discriminant analysis confirmed these
Conclusions: We demonstrated that the UPS and
autophagy were activated during long-term disease in humans. We also
found a set of proteins whose expression levels may be specific of the
atrophying process. These proteins constitute potential biomarkers
witnessing the activation of muscle atrophy and/or potential therapeutic
Body composition and sarcopenia before and after surgery for oesophageal cancer
Ulrika Smedh, Jan Persson, Monika Fagevik Olsen and Britt-Marie Iresjö
University of Gothenburg, Gothenburg, Sweden
The occurrence of dysphagia is a well-known feature of oesophageal
cancer that may reduce caloric intake. Body composition alterations and
prevalence of sarcopenia in patients with oesophageal cancer before and
after surgery are not well known, and their possible consequences have
been debated. The aim was to describe biometric measures including body
composition, and sarcopenia, physical performance, dysphagia, as well as
quality of life (QoL) in a cohort of patients with oesophageal cancer
before surgery with curative intent. In addition, we aimed to
investigate alterations in body composition as a consequence of the
surgery at 1 and 3 months post-operatively. Moreover, to investigate if
pre-operative biometric measures, or sarcopenia, are correlated to
morbidity, length of stay, QoL or mortality.
observational study was performed in a cohort of 76 patients who had
oesophageal or cardia cancer and were planned for open surgery with
curative intent. Demographic data and data on body composition measured
with bioimpedance, working capacity (cardiac stress test), grip strength
and QoL (EORTC QLQ-C30 version 3.0) were prospectively collected from
the patient history database. Data regarding dysphagia was derived from
the oesophagus-related QoL form EORTC QLQ-OES18. Data on tumour stage
and type, complications, length of stay, weight loss and nutritional
state were also collected.
Results: Pre-operatively the
patients displayed normal BMI despite that almost 20% were sarcopenic,
86% had a lowered physical performance level and 37% of the patients
were judged severely malnourished. All body composition variables except
fat mass were declined up to 3 months after surgery. No pre-operative
biometric measure or QoL item was correlated with risk for
complications. BMI was positively correlated to length of stay at the
intensive care unit. Female sex and malnourishment showed significantly
fewer ICU days. High physical performance, female sex and high global
QoL score positively predicted overall survival.
Severe malnourishment was common in patients planned for oesophageal
resection due to cancer in spite of normal BMI. Neither pre-operative
malnutrition (SGA C) nor sarcopenia were independent risk factors for
morbidity or overall mortality in patients judged suitable for surgery.
However, oesophageal resection surgery caused long lasting catabolic
effects, highlighting the importance of optimal peri- and post-operative
skeletal muscle quality and sarcopenic obesity are associated with
postoperative morbidity after neoadjuvant chemoradiation and resection
for rectal cancer
Annefleur E.M. Berkel1, Joost M. Klaase1, Feike de Graaff2, Marjolein G.J. Brusse-Keizer3, Bart C. Bongers4 and Nico L.U. van Meeteren4,5
1Department of Surgery, Medisch Spectrum Twente, Enschede, The Netherlands; 2Faculty of Science and Technology, University of Twente, Enschede, The Netherlands; 3Medical School Twente, Medisch Spectrum Twente, Enschede, The Netherlands; 4Department
of Epidemiology, School for Public Health and Primary Care (CAPHRI),
Maastricht University, Maastricht, The Netherlands; 5Health~Holland, Topsector Life Sciences and Health, The Hague, The Netherlands
This explorative retrospective study investigated the relation between
skeletal muscle measurements (muscle mass, muscle quality and sarcopenic
obesity), and postoperative morbidity and survival after neoadjuvant
chemoradiation followed by non-laparoscopic resection for rectal cancer.
Ninety-nine consecutive patients who underwent neoadjuvant
chemoradiation and surgery between January 2007 and May 2012 were
identified. Skeletal muscle mass was measured as total psoas area and
total abdominal muscle area at three anatomical levels using the
patient's preoperative computed tomography scan. Skeletal muscle quality
was measured using corresponding mean Hounsfield Units for total
abdominal muscle area. Sarcopenic obesity was defined as body mass index
above 25 kg·m−2 combined with skeletal muscle mass measures
below the sex-specific median. Postoperative complications were graded
according to the Clavien-Dindo classification.
Twenty-five patients (25.3%) developed a severe complication. Lower
skeletal muscle quality was independently associated with overall (p = 0.007) and severe complications (p = 0.002). Sarcopenic obesity was associated with overall complications (all p < 0.05). No significant relations were found between skeletal muscle measurements and survival.
Skeletal muscle quality is associated with overall and severe
postoperative morbidity after neoadjuvant chemoradiation and
non-laparoscopic resection for rectal cancer. Sarcopenic obesity is
associated with overall complications.
Functional muscle strength is associated with muscle mass in patients with esophageal cancer awaiting surgery
Maarten A. van Egmond1,2,3, Marike van der Schaaf1,2, Eliza R.C. Hagens5, Hanneke W.M. van Laarhoven4,6, Mark I. van Berge Henegouwen5,6, Liesbeth B. Haverkort7,8,9, Raoul H.H. Engelbert1,2 and Suzanne S. Gisbertz5,6
1Department of Rehabilitation, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2ACHIEVE, Center of Applied Research, Amsterdam University of Applied Sciences, Faculty of Health, Amsterdam, The Netherlands; 3European School of Physiotherapy, Amsterdam University of Applied Sciences, Faculty of Health, Amsterdam, The Netherlands; 4Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 5Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 6Cancer Center Amsterdam, Amsterdam, The Netherlands; 7Research Centre for Innovations in Health Care, University of Applied Sciences, Utrecht, The Netherlands; 8Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands; 9Department of Dietetics, Academic Medical Center, Amsterdam, The Netherlands
Decreased muscle mass and muscle strength are independent predictors of
postoperative complications and poor postoperative recovery in patients
with esophageal cancer. The association between muscle mass and muscle
strength is not self-evident. If the association between muscle mass and
muscle strength in preoperative patients with esophageal cancer is
known, physiotherapists are able to measure functional muscle strength
as an early predictor for the consequences for functional performance
due to decreased muscle mass and eventually sarcopenia.
To investigate the association between muscle mass and functional
muscle strength in patients with esophageal cancer awaiting
esophagectomy before neoadjuvant chemoradiation.
In patients with resectable esophageal cancer eligible for surgery
between March 2012 and October 2015, Computed Tomography scans were used
to assess muscle mass and compared with functional strength measures
(hand grip strength, inspiratory- and expiratory muscle strength,
30 seconds chair stands test). Pearson correlation coefficients were
calculated, and associations were determined by multivariate linear
Results: 126 subjects were referred to
physiotherapy from a tertiary referral center and were eligible for the
study; 94 subjects were finally included for statistical analysis.
Multiple backward regression analysis showed that gender (95% CI –32.4,
−2.2), weight (95% CI 0.4, 1.0), age (95% CI –0.9, −0.7), non-dominant
handgrip strength (95% CI 0.2, 1.5) and inspiratory muscle strength (95%
CI 0.1, 0.4) were all independently associated with muscle surface area
at L3. All these variables together explained 65% of the variability (R2) in muscle surface area at L3 (p < 0.001).
This study shows an independent association between aspects of
functional muscle strength and muscle mass in patients with esophageal
cancer awaiting surgery, and the results could be used by
physiotherapists to predict muscle mass based on functional muscle
strength in preoperative patients with esophageal cancer.
addition of sarcopenia does not surpass the MELD score in predicting
waiting list mortality in cirrhotic liver transplant candidates
Jeroen L.A. van Vugt1, Louise J.M. Alferink2, Stefan Buettner1, Marcia P. Gaspersz1, Daphne Bot3, Sarwa Darwish Murad2, Shirin Feshtali4, Peter M.A. van Ooijen5, Wojciech G. Polak1, Robert J. Porte6, Bart van Hoek7, Aad P. van den Berg8, Herold J. Metselaar2 and Jan N.M. IJzermans1
1Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands; 2Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; 3Department of Dietetics, Leiden University Medical Center, Leiden, The Netherlands; 4Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; 5Department of Radiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; 6Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; 7Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; 8Department
of Gastroenterology and Hepatology, University of Groningen University
Medical Center Groningen, Groningen, The Netherlands
Frail patients with low MELD scores may be underprioritized. Recently,
low skeletal muscle mass (i.e. sarcopenia) has been identified as a risk
factor for waiting list mortality and a study proposed to include
sarcopenia in the MELD score (i.e. MELD-Sarcopenia score). We aimed to
investigate the association between sarcopenia and waiting list
mortality and to validate the MELD-Sarcopenia score
(MELD + 10.35*Sarcopenia).
Patients and methods: Using the
Eurotransplant registry, consecutive patients with cirrhosis listed for
liver transplantation between 2007 and 2014 were identified. Survival of
patients with and without sarcopenia was compared using Fine and Gray
Competing Risks Analysis. Performance of the MELD, MELDNa and
MELD-Sarcopenia score was investigated using concordance (c) indices
after bootstrapping crossvalidation. Variables in the multivariable
analysis were selected based on the Akaike Information Criterion.
In total, 588 patients were included with a median MELD of 14 (IQR
9–19), of which 225 (43.4%) were identified as having sarcopenia. Median
waiting list survival was 5 months. Both the sarcopenia cut-offs
according to Carey and according to Martin were not significantly
associated with survival in univariable analysis. The discriminative
performance of the MELD-Sarcopenia score for 5 months (c-index 0.668)
was comparable to the MELD score alone (c-index 0.663) and the MELDNa
score (c-index 0.666). Apart from the MELD score with or without
sarcopenia, other independent predictive variables were occurrence of
hepatic encephalopathy before listing, and recipient albumin at the time
Conclusions: Sarcopenia as an addition to the
MELD score did not improve prognostic ability when analysed using
competing risks regression in a Dutch national cohort. Other measures of
sarcopenia did not reach significance in univariable analysis.
Resting Energy Expenditure (REE) of children with End Stage Liver Disease (ESLD)
Eirini Kyrana1, Jane E. Williams2, Jonathan C.K. Wells2 and Anil Dhawan1
1King's College Hospital, London, UK; 2Institute of Child Health, London, UK
Introduction: Hypermetabolism has been described in patients with ESLD, as measured REE (mREE) ≥ 120% of predicted REE (pREE).
REE was quantified by indirect calorimetry. Seventeen children (mean
age 7.6 yrs/ median 6.9 yrs) with ESLD had their mREE prior to having a
liver transplant. Valid results were in sixteen. pREE was calculated
from the Henry 2005 equations. REE was measured and predicted for
thirteen healthy children (mean age 8.3 yrs/ median 8 yrs). Twelve had
valid results. Children over 4 years of age from both groups had fat
free mass (FFM) determined with air displacement plethysmography (BOD
Results: The differences in mean age, mean mREE/kg of
body weight (BW) and RQ between the patients and healthy controls were
not significant (NS). Seven of the 16 patients (44%) were
hypermetabolic, and 9/16 were normometabolic (56%). Mean RQ for both
groups was 0.77.
6 of the 12 (50%) healthy controls were
hypermetabolic. The mean RQ for the hypermetabolic healthy children was
0.75 and for the normometabolic 0.79 (NS). Differences of mean SD scores
for BW, height and BMI between hypermetabolic and normometabolic groups
of patients and healthy children did not achieve statistical
significance. 8 patients and 10 healthy controls had FFM measured with
BOD POD. Mean mREE/kg of FFM for the patients was 57.53 Kcal/kg and for
the healthy controls 59.5 Kcal/kg (NS). Nine of the patients had their
liver transplant and had mREE at a median of 10.8 months
post-transplant. The differences in mean REE/kg and RQ before and after
liver transplantation were not statistically significant. REE/kg pre
transplant correlated significantly with REE/kg post-transplant (r = 0.832, p = 0.005).
mREE and the presence of hypermetabolism was not different between
children with ESLD awaiting liver transplant and healthy controls.
mREE/kg after transplant correlated significantly with mREE/kg before
walk distance is superior to Karnofsky Performance Status to predict
mortality in candidates for liver transplantation
Elizabeth J. Carey1 and Bridgette McNally2
1Mayo Clinic, Phoenix, USA; 2Midwestern University Arizona College of Ostepathic Medicine, Phoenix, USA
Poor functional status is associated with increased mortality in
cirrhosis patients awaiting liver transplantation; however, the optimal
assessment of functional status remains unknown. This study sought to
determine the relationship between six-minute walk distance (6MWD) and
Karnofsky Performance Status (KPS) and their association with waitlist
mortality (WLM) in liver transplant (LT) candidates.
Two hundred seventy-eight consecutive patients listed for LT at a
single institution were included. KPS and 6MWD were assessed at the time
of LT evaluation. KPS scores were recorded as a percentage from 0 to
100, with 0 representing death and 100 representing no presence of
disease. Patients were followed from time of listing until
transplantation, death, removal from the waitlist or end of the study
period (study period: 01/2014–03/2017).
Results: The mean
KPS and 6MWD were 77.4 ± 13.5 and 323.6 ± 163.9 m, respectively. A mild
correlation between 6MWD and KPS was demonstrated (Spearman ρ = 0.4317, p < 0.0001). KPS score was significantly lower in patients with 6MWD <250 meters (p < 0.0001).
In univariate and multivariate logistic regression, there was no
significant relationship between KPS score and waitlist mortality. In
contrast, the 6MWD was significantly lower in patients who suffered
waitlist mortality (266.1 vs 331.8, p = 0.05) and was the only
significant predictor of WLM in multivariate logistic regression. HCC
patients were shown to be less likely to die on the waitlist compared to
other liver disease etiologies.
conclusion, 6MWD is a better predictor of waitlist mortality than KPS
score in candidates for LT. The addition of 6MWD as a standard
assessment may help to identify patients at risk of dying on the
Sarcopenia in liver transplant due to Familial Amyloidotic Polyneuropathy (FAP): the relevance of muscle mass
Maria Teresa Tomás1,2, Xavier Melo2,3, Élia Mateus4, Eduardo Barroso4 and Helena Santa-Clara2
1Lisbon Higher School of Health Technology (ESTeSL) at Lisbon Polytechnique Institute, Lisbon, Portugl; 2Interdisciplinary
Centre for the Study of Human Performance (CIPER) at Faculdade de
Motricidade Humana – Universidade de Lisboa, Portugal; 3Ginásio Clube Português; 4Hepatobiliopancreatic and Transplantation Centre at Hospital Curry Cabral, Lisbon, Portugal
Loss of muscle mass and function is a common occurrence in liver
transplant Familial Amyloidotic Polyneuropathy (FAP) patients.
Sarcopenia is associated with morbidity and mortality before and after
liver transplantation. However, the ability of skeletal muscle mass to
recover after transplant remains questionable and thus the importance of
clinical exercise prescription.
Methods: Participants were
39 FAP patients aged 23–59 years, who had been submitted to a liver
transplant (Tx) (22 men) between 2 and 4 months post-tx. Sarcopenia was
defined according to the International Working Group on Sarcopenia and
Society of Sarcopenia, Cachexia and Wasting Disorders. Whole-body dual
x-ray absorptiometry was used to measure body fat and lean-soft tissue.
Skeletal Muscle Index (SMI) was calculated adjusting the value of
appendicular skeletal mass to the squared height. Functional aerobic
capacity was assessed using the 6 min walk test (6MWT), and handgrip
strength was measured on the dominant hand using a hand dynamometer.
The prevalence of sarcopenia using SMI was 45.5% in men and 41.2% in
women. A fat mass higher than 16% for men and 26% for women was found in
54.5% of men and 52.9% of women. Also 27.3% of men and 17.6% of the
women could be classified as having sarcopenia with low mobility
(distance < 400 m).
Discussion and Conclusions:
Sarcopenia is common in FAP patients and a liver transplant seems to
increase the prevalence, also because an aggressive medication with
impact on muscle metabolism should be made longtime. More data are
needed on the long-term effects of sarcopenia after transplant,
especially in light of the high rate of metabolic syndrome.
clinical exercise prescription seems to be necessary for these patients
but more studies are needed (e.g. longitudinal studies).
Diagnosing sarcopenia in patients with cirrhosis, ascites and lower limb edema
Giliane Belarmino1, Maria Cristina Gonzalez2,3, Priscila Sala1, Raquel Susana Torrinhas1, Wellington Andraus1, Luiz Augusto Carneiro D'Albuquerque1, Rosa Maria R. Pereira4, Valéria F. Caparbo4, Steven B. Heymsfield3 and Dan L. Waitzberg1
1Department of Gastroenterology (LIM 35), Surgical Division, Faculdade de Medicina da Universidade de São Paulo, Brazil; 2Postgraduate program in Health and Behavior, Universidade Católica de Pelotas, Rio Grande do Sul, Brazil; 3Pennington Biomedical Research Center, Baton Rouge, LA, USA; 4Laboratory of Bone Metabolism, Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Brazil
Ascites limit skeletal muscle mass assessment. We propose that
sarcopenia diagnosis in cirrhosis can be improved by using dual-energy
X-ray absorptiometry to calculate the appendicular skeletal muscle index
(DXA-ASMI), as it bypasses the abdominal compartment.
We evaluated whether DXA-ASMI is influenced by ascites or lower limb
edema (LLE) and can be applied to diagnose sarcopenia with prognostic
value for mortality, alone or combined with non-dominant handgrip
Design: DXA-ASMI and ND-HGS values were
obtained and 36 months mortality recorded in 144 male cirrhotic
patients. DXA-ASMI was calculated pre- and post-paracentesis in 20
patients with ascites and compared with data from 20 matched volunteers.
DXA-ASMI values obtained from patients with and without LLE were
compared. Prognostic value of DXA-ASMI and DXA-ASMI + ND-HGS was tested
in a final survival model adjusted for MELD and age. Survival
probabilities were obtained for sarcopenia diagnosed by standard cutoffs
for DXA-ASMI and ND-HGS values (EWGSOP) and a new cutoff calculated
from our DXA-ASMI + ND-HGS tertiles.
Results: DXA-ASMI did not differ pre- and post-paracentesis, were lower in cirrhotic patients than in volunteers (p < 0.001), and were not influenced by LLE (mean difference = 0.30 kg/m2, p = 0,068; R2 = 2.40%). Mortality was influenced by DXA-ASMI and ND-HGS (pinteraction = 0.028).
Sarcopenia diagnosed by EWGSOP was also diagnosed by our new cutoff;
both predicted mortality, but the latter was more sensitive for
mortality risk prediction (p = 0.011).
In cirrhosis, DXA-ASMI estimates are not influenced by ascites or LLE
and can identify low skeletal muscle mass for diagnosing sarcopenia with
prognostic value for mortality, mainly when combined with ND-HGS.
Low skeletal muscle mass is associated with increased hospital costs in patients with cirrhosis listed for liver transplantation
Jeroen L.A. van Vugt1, Stefan Buettner1, Louise J.M. Alferink2, Niek Bossche3, Ron W.F. de Bruin1, Sarwa Darwish Murad2, Wojciech G. Polak1, Herold J. Metselaar2 and Jan N.M. IJzermans1
1Department of Surgery, Division of HPB and Transplant Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands; 2Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; 3Department of Control and Compliance, Erasmus MC University Medical Center, Rotterdam, the Netherlands
Low skeletal muscle mass (sarcopenia) is associated with increased
morbidity and mortality in liver transplant candidates. We investigated
the association between sarcopenia and hospital costs in patients listed
for liver transplantation.
Methods: Consecutive patients
with cirrhosis listed for liver transplantation between 2007 and 2014 in
a Eurotransplant center were identified. The skeletal muscle index
([SMI], cm2/m2) was measured on CT performed
within 90 days from waiting list placement. The lowest sex-specific
quartile represented patients with sarcopenia.
total, 224 patients were included. Median time on the waiting list was
169 (IQR 46–306) days, and median MELD-score was 16 (IQR 11–20). The
median total hospital costs in patients with sarcopenia were €11,294
(IQR 3,570–46,469) compared with €6,878 (IQR 1,305–20,683) in patients
without sarcopenia (p = 0.008). In multivariable regression
analysis, an incremental increase in SMI was significantly associated
with a decrease in total costs (€458 per incremental SMI, 95%CI 14–902, p = 0.043), independent of the total time on the waiting list.
In conclusion, sarcopenia is independently associated with increased
health-related costs for patients on the waiting list for liver
transplantation. Optimizing skeletal muscle mass may therefore lead to a
decrease in hospital expenditure, in addition to greater health benefit
for the transplant candidate.
Body composition in extreme small stature adults: the case of mucopolysaccharidosis
Bhawna Sharma1,2, Boyd Strauss2, Christian Hendriksz1,3 and Gisela Wilcox1,2
1Mark Holland Metabolic Unit, Salford Royal NHS Foundation Trust, UK; 2Faculty of Biology, Medicine and Health, University of Manchester, UK; 3Steve Biko Academic Unit, University of Pretoria, South Africa
The mucopolysaccharidoses (MPS) are a group of rare inherited metabolic
disorders due to the accumulation of glycosaminoglycans (GAGs) within
lysosomes. Accumulation of GAGs in different tissues causes significant
multi-systemic complications, associated with, in many cases, extreme
short stature. Hydrophilic GAGs may alter body composition, but
measurement has not yet been explored in the literature.
We aimed to assess if patients with MPS have a different body
composition to that of the general population and to investigate in
which body composition compartment GAGs accumulate predominantly.
Eleven MPS patients attending the adult inherited metabolic medicine
clinic at Salford Royal Foundation Trust were measured using the
multifrequency segmental SECA BIA 515. These data were compared to data
from healthy European individuals.
Results: In the 11
patients with MPS, weight was significantly correlated with fat mass,
but not percentage fat. Weight was also highly correlated with fat-free
mass and skeletal muscle mass, even after correction for height. Height
was significantly correlated with fat-free mass and skeletal muscle
Patients with MPS have a significantly reduced stature, mass
and phase angle, and significantly increased resistance to current
flow, when compared to the general population.
The question of whether or not extreme small stature affects body
composition is not yet resolved. The correlation between both weight and
height, and skeletal muscle mass, could be accounted for by GAG
accumulation in skeletal muscle; other body composition techniques,
especially for muscle mass, need to be applied to this group and methods
for estimating tissue GAG mass developed. This group challenges
conventional definitions of sarcopenia.
Phase angle and sarcopenia: are they related?
Jéssica Härter1, Silvana Paiva Orlandi1 and Maria Cristina Gonzalez1,2
1Post-graduate Program, Nutrition and Food, Federal University of Pelotas, Pelotas, RS, Brazil; 2Post-graduate Program, Health and Behavioral, Catholic University of Pelotas, Pelotas, RS, Brazil
Phase angle (PA) has been considered as a prognostic factor for several
clinical conditions, probably because of its relationship to fat-free
mass and function. More recently, decreased muscle mass and functional
assessment were used to define sarcopenia. The purpose of this work was
to identify the relationship of PA, sarcopenia and its components in
Methods: Fifty-nine cancer patients
hospitalized for elective surgery were studied. Bioelectrical impedance
analysis (BIA Quantum II, RJL Systems®) was performed in all patients
and skeletal muscle index, using Janssen equation, and PA and
Standardized Phase Angle (SPA) were estimated, using reference values
from this population. The handgrip strength was obtained using Jamar®
hydraulic dynamometer, and gait speed was assessed by using 4-m test.
The diagnosis of sarcopenia was performed according the European Working Group on Sarcopenia in Older People.
Malnutrition was assessed by Patient-generated Subjective Global
Assessment. The outcomes evaluated were postoperative complications
(Clavien–Dindo classification) and length of stay (LOS).
Sarcopenia was present in 17% of the patients and malnutrition in
30.5%. SPA was significantly lower in malnourished (−0.20 vs. 0.62 p = 0.028) and sarcopenic patients (−0.39 vs. 0.59 p = 0.010). Patients with a lower handgrip strength (−0.31 vs. 0.69 p = <0.001) and slower gait speed (−0.30 vs. 0.60 p = 0.016)
also showed a lower SPA. SPA and PA from non-sarcopenic patients with
impaired functions also showed a lower SPA and PA than those with normal
function. Patients with serious postoperative complications (−0.71 vs.
0.41 p = 0.007) and longer LOS (−0.16 vs. 0.64 p = 0.030) presented lower SPA. The same results were found when PA (adjusted for sex and age) was used.
PA was decreased in all the sarcopenia components, and it has been
associated with impaired nutritional and functional status in this
French translation and validation of the sarcopenia screening tool SARC-F
Charlotte Beaudart1, Médéa Locquet1, Stephen Bornheim2, Stéphane Schneider3, Jean-Yves Reginster1 and Olivier Bruyère1
1Research Unit in Public Health, Epidemiology and Health Economics (URSAPES), University of Liège, Liège, Belgium; 2Unité de Kinésithérapie générale, CHU Liège, Liège, Belgium; 3Centre Hospitalier Universitaire de Nice, Pôle Digestif, Université de Nice Sophia-Antipolis, Faculté de Médecine, Nice, France
The purpose of the present study was to translate into French the
SARC-F questionnaire, a simple and easy screening tool for sarcopenia,
and then to validate this translated/French version on behalf of the
EUGMS Special Interest Group (SIG) on Sarcopenia.
The translation process has been divided into two consecutive parts: 1)
the translation of the questionnaire from English to French and its
language validation (inter-rater reliability and test–retest
reliability); 2) the clinical validation of the French SARC-F in order
to assess its performance (sensitivity, specificity, predictive positive
value and predictive negative value) in a cohort of Belgian elderly
subjects, against seven existing definitions of sarcopenia.
The translation from English to French has been performed without any
difficulties and demonstrated an excellent inter-rater reliability with
an ICC of 0.90 (95% CI: 0.76–0.96) as well as an excellent test–retest
reliability with an ICC of 0.86 (95% CI: 0.66–0.94). Afterwards, 306
subjects took part in the clinical validation of the French version of
the SARC-F questionnaire. Results showed that the sensitivity of the
tool ranged from 22.1% to 75.0%, depending on the definition used for
the diagnosis of sarcopenia, and the specificity ranged from 84.9% to
87.1%. Moreover, all PPVs were below 50%; the lowest PNV was 68.1% and
the best one reached around 99%.
Conclusions: The results
are in line with the performance established in the initial English
validation of the SARC-F and seem to indicate that this screening tool
can detect with precision the absence of sarcopenia but seems less
precise in affirming the presence of this geriatric syndrome.
SarQoL®, a specific quality of life questionnaire for sarcopenia, is
adapted to identify 1-year decrease in quality of life related to muscle
Charlotte Beaudart, Médéa Locquet, Laura Delandsheere, Jean-Yves Reginster and Olivier Bruyère
Research Unit in Public Health, Epidemiology and Health Economics (URSAPES), University of Liège, Liège, Belgium
Our aim was to assess the impact of 1-year change in musculoskeletal
health on quality of life (QoL) using the SarQoL® questionnaire, a
quality of life questionnaire specific for sarcopenia.
Three QoL questionnaires (the SarQoL® and two generic QoL
questionnaires, the EQ-5D and the SF-36) have been completed by 301
subjects from the SarcoPhAge study (Sarcopenia and Physical impairments with advancing Age, a cohort developed in Belgium). Muscle mass (ALM/h2,
assessed with DXA), grip strength (assessed with hydraulic dynamometer)
and gait speed were evaluated. Sarcopenia was diagnosed according to
the EWGSOP algorithm.
Results: After one year of follow-up, the QoL of the general population (75.0 ± 5.97 years, 59% women) decreased (p < 0.001 with the SarQoL®, p = 0.03 with the EQVAS, p < 0.001 with the EQ-5D). The ALM/h2 was not significantly modified but a decrease in muscle strength, and gait speed was observed (p < 0.001
for both). A significant correlation was found between 1-year decrease
in gait speed and 1-year decrease in QoL only when using the specific
questionnaire SarQoL®, but not when using the generic EQ-5D or EQVAS
tools. Results indicated a correlation of r = 0.21 (p < 0.001) for the whole cohort population and r = 0.41 (p = 0.013) for the sarcopenic elders (n = 38). These associations were not observed for muscle mass (p = 0.65) or muscle strength (p = 0.06).
Using a multivariate regression the association between decreased gait
speed and decreased QoL, assessed with the SarQoL®, was significant,
independently of age, sex, number of comorbidities and number of drugs
(p < 0.001 for both whole cohort and sarcopenic subjects).
Our findings suggest that a decrease in physical performance and more
specifically in gait speed is associated with a decrease in QoL in
elders and more specifically in those suffering from sarcopenia. The
specific SarQoL® seems better adapted than generic tools to identify
decrease in QoL related to muscle function.
from the use of the SARC-F questionnaire associated with calf
circumference as a sarcopenia screening tool in a Brazilian population
Thiago G. Barbosa-Silva1, Letítia Mazocco2, Patrícia Chagas3 and Maria Cristina Gonzalez4
1Programa de Pós-Graduação em Epidemiologia da Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil; 2Programa de Pós-graduação em Gerontologia da Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil; 3Departamento
de Alimentos e Nutrição e Programa de Pós-graduação em Gerontologia da
Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil; 4Programa de Pós-Graduação em Saúde e Comportamento da Universidade Católica de Pelotas (UCPEL), Pelotas, RS, Brazil
SARC-F + CC was recently proposed as a variation of the SARC-F
questionnaire, combining its questions (which evaluate muscle function)
with an anthropometric measurement (calf circumference (CC), as a
surrogate for muscle mass]. However, SARC-F + CC still lacks validation.
Objective: Evaluating SARC-F + CC's performance as a sarcopenia screening tool.
Cross-sectional study including elderly women (≥60 years old) who
performed bone densitometry for clinical purposes. Sarcopenia was
defined by the EWGSOP's recommended criteria: muscle mass evaluation
through dual-energy X-Ray absorptiometry (DXA), muscle strength
evaluation by handgrip strength and muscle performance evaluation
through the 4-m gait speed test. Specific cut-off reference values for
the Brazilian population were used to define low Appendicular Skeletal
Muscle Mass Index (ASMI) from DXA (5.62 kg/m2) and CC
(≤33cm). The Brazilian version of SARC-F was applied, and 10 points were
added to the SARC-F score if the subjects had a low CC. Subjects with a
final score ≥11 were considered as at sarcopenia risk.
A total of 205 elderly women (mean age: 67.3 ± 5.9 years) were included
in the study. The majority of the sample lived in rural areas (65.9%)
were Caucasian (71.2%), had 4–8 years of schooling (47.3%), lived with a
partner (61.5%) and were retired (92.2%). Applying EWGSOP criteria, the
prevalence of sarcopenia was 2.4% of the total sample (5 subjects).
Through SARC-F + CC, 37 women (18%) were identified as in risk for
sarcopenia. Although SARC-F + CC presented low sensitivity (40%) and
positive predictive value (5.4%), it performed well in identifying
healthy participants (specificity: 82.5%) and had an excellent negative
predictive value (98.2%).
Conclusions: This study confirms
previous published findings which suggest that the combination of
SARC-F + CC, using specific regional cut-off values for CC, can be used
to rule out healthy subjects from further testing, improving sarcopenia
screening in clinical practice.
A cross-sectional study on sarcopenia: association between muscle mass and strength and metabolic syndrome in Saudi men
Shaea Alkahtani1, Sobhy Yakout2 and Nasser Al-Daghri2
1Department of Exercise Physiology, College of Sports Science and Physical Activity, King Saud University, Riyadh, Saudi Arabia; 2Prince
Mutaib bin Abdullah Chair for Biomarkers Research on Osteoporosis,
College of Science, King Saud University, Riyadh, Saudi Arabia
The mean value of appendicular lean mass (ALM) in Saudi young men has
been recently determined and was different from those of other
ethnicities. Whether ALM is associated with increased metabolic syndrome
among Saudis has not been examined.
Aim: The aim was to determine the association between ALM, muscle strength and metabolic syndrome in Saudi men.
Participants included 497 Saudi men aged between 20 and 77 years. Hand
grip and thigh strength was measured, and lean muscle mass was assessed
using dual-energy X-ray absorptiometry (DXA). Venous blood samples were
collected to assess metabolic syndrome markers.
Results: There were 14.9% of participants who had low ALM/Ht2
(2SD below reference value of Saudi young men). Handgrip and thigh
strength were significantly lower among sarcopenic group (37.9 ± 7.1 vs
43.4 ± 7.5, p < 0.001 and 63.5 ± 24.3 vs 76.6 ± 23.5, p < 0.001,
respectively). Metabolic Syndrome was 17.7% of participants, and 8.1% of
them were classified as sarcopenic. There were no significant
differences between sarcopenic and normal group in metabolic syndrome
factors, but there was correlation between total cholesterol and ALM/Ht2 in sarcopenic group (r = 0.24). 63.9% of participants were obese (BMI > 30 kg/m2).
Sarcopenic group had significantly lower level of fat compared with
normal group, and the decrease was found in trunk and arms, but not legs
(p = 0.27).
Conclusions: There was no association
between low lean mass and metabolic syndrome in Saudi men.
Socioeconomic factors that interact with current data have to be
Prevalence of sarcopenia in patients with cachexia and disease-related malnutrition
Igor Khoroshilov1 and Sergei Ivanov2
1North-Western State Medical University named after I.I. Mechnikov, St. Petersburg, Russian Federation; 2Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
Aim: The sarcopenia prevalence assessment in patients with cachexia and disease-related malnutrition.
44 patients (16 men, 28 women) with undernutrition (BMI less than
18.5 kg/m2) held the treating in 2012–2016 years were included into
retrospective analyze. Sarcopenia was identified by criteria suggested
G. Biolo, T. Cederholm and M. Muscaritoli (2014): fat-free mass index
(FFMI) less than 17 kg/m2 for men and less than 15 kg/m2 for women. Bioimpedance analysis and dual energy X-ray absorptiometry were used for FFMI evaluating.
It has been found that FFMI in the patients with cachexia and
precachexia with inflammation (cancer, Crohn's disease, ulcerative
colitis, sepsis etc.) were 13.96 1.4 kg/m2, particularly 13.5 0.47 kg/m2 in 7 women and 14.3 0.49 kg/m2
in 9 men. Sarcopenia was found at all of 16 patients with cachexia and
precachexia (100%). At 28 patients with chronic and acute
disease-related malnutrition (without inflammation) FFMI were 13.7
0.4 kg/m2, particularly 13.7 0.46 kg/m2 in 21 women and 13.7 1.2 kg/m2
in 7 men. In patients without inflammation sarcopenia had been observed
in 19 persons (68%). Significant differences in FFMI were found between
patients with sarcopenia but without inflammation (FFMI was 12.68
0.49 kg/m2) and patients with sarcopenia combined with cachexia (P < 0.05).
Sarcopenia is observed at all of patients with cachexia and
precachexia. Among patients with undernutrition without inflammation the
sarcopenia was observed at 68% of them.
Muscle thickness measured by A-mode ultrasound in prediction of total lean body mass in apparently healthy adults
M. Bielemann, Mariana O. Xavier, Arele R. Nunes, Rafaela B. Bergmann,
Silvana P. Orlandi, Thiago G. Barbosa-Silva, Maria Cecília Assunção and
Maria Cristina Gonzalez
Federal University of Pelotas, Brazil, Catholic University of Pelotas, Brazil
In the last decades, ultrasound (US) has emerged as a promising tool to
assess body composition, especially in situations where the assessment
of muscle mass should be done at bedside. To evaluate the relationship
between muscle thicknesses in various body regions and total lean soft
tissue in adults.
Methods: Cross-sectional study with 208
individuals between 20 and 59 years from Pelotas, Brazil. Muscle
thicknesses of biceps, triceps, thigh and calf regions were measured by
A-mode ultrasound (BodyMetrix®). Arm, thigh and leg circumference and
length were also measured. Lean soft tissue index (LSTI) (kg/m2)
was obtained by total lean body mass from DXA divided by squared
height. The highest muscle thickness from eight ultrasound measurements
in each region was used in the analyses. Pearson correlation
coefficients were obtained between muscle thickness of regions of the
upper and lower limbs and LSTI. Adjusted coefficients of determination
(R2) were described to show the explained variance in LSTI
promoted by addition of each anthropometric information from linear
Results: Muscle thickness from thigh showed the highest correlation coefficient with LSTI in both men (r = 0.68) and women (r = 0.52).
Correlation coefficients of sum of muscle thickness from the four
regions and LSTI was 0.78 in men and 0.58 in women. Around 62% and 36%
of variance in LSTI was explained by the sum of muscle thickness in the
four regions. Arm, thigh and leg length did not increase the R2, but arm, thigh and leg circumference increased the R2
to around 69% and 44% in men and women, respectively. Body weight did
not add explanation in LSTI after use of all other anthropometric
Conclusions: The results demonstrated that
the A-mode ultrasonography has shown good predictive value of LSTI in
apparently healthy men, mainly in set with other anthropometric
Can phase angle detect differences among nor-sarcopenic patients with impaired function?
Maria Cristina Gonzalez1, Jaqueline Flores de Oliveira1, Inara Regina Frühauf2, Eduarda Jaine Facchinello Dall'Aqua2, Jean Pierre Oses1, Maristela Bohlke1 and Rafael Orcy and Thiago Gonzalez Barbosa-Silva3
1Programa de Pós-Graduação em Saúde e Comportamento da Universidade Católica de Pelotas (UCPEL), Pelotas, RS, Brazil; 2Graduação em Medicina da Universidade Católica de Pelotas (UCPEL), Pelotas, RS, Brazil; 3Programa de Pós-Graduação em Epidemiologia da Universidade Federal de Pelotas (UFPEL), Pelotas, RS, Brazil
The European Working Group on Sarcopenia in Older People (EWGSOP)
considered muscle mass loss to identify sarcopenic (S) or pre-sarcopenic
(PS) patients. However, loss of function without muscle mass loss, here
called “functionally impaired with normal muscle mass” (FINMM), may
determine a different prognostic risk. The objective of this study is to
use Phase angle (PA), a prognostic marker in several clinical
situations, and compare its values between FINMM and patients with
normal muscle mass and function in non-sarcopenic (NS) patients.
Sarcopenia was assessed according to EWGSOP criteria. The muscle mass
was evaluated through the calf circumference (CC), using validated
cut-offs for this population. Muscle strength and performance were
assessed by handgrip strength and 4-m gait speed test. PA was assessed
with a Bioelectrical impedance analysis device, using resistance and
reactance from 50 kHz.
Results: A sample of 82 patients
with a mean age of 53.9 ± 16.9 years were studied. PS was present in
4.9% of the sample, and sarcopenia in 32.9% (27 patients). There were no
significant differences in PA values among NS (5.91° ± 1.31°), PS
(6.65° ± 1.54°) and S patients (5.38° ± 1.27 ). Only severe sarcopenic
patients had PA values significantly lower than NS and PS patients. From
the 51 patients identified as NS, 34 patients were considered FINMM.
When normal and FINMM patients were compared, it was found that PA
values from FINMM patients were significantly lower than normal patients
(5.46° ± 1.11°× 6.82° ± 1.22°, p = 0.003), and they were not significantly different from PA values found in PS or S patients.
The lower PA values found in FINMM patients may suggest that they
should be identified as a special risk group among non-sarcopenic
patients. Longitudinal studies may show the increased morbidity and
mortality in this group.
SARA-data platform: clinical trials novel methodologies and big data to evaluate SARconeos in Age-related sarcopenia
Susanna Del Signore1,2, Gianluca Zia1, Stefania Del Signore1 and Waly Dioh2
1Bluecompanion ltd, London, UK; 2Biophytis, Paris, France
SARA clinical development program encompasses one observational study
and two randomized, placebo controlled clinical trials for evaluating
the candidate drug SARconeos (BIO101) in sarcopenic and obese sarcopenic patients Aged ≥65 years.
We deployed an integrated Information & Communication Technology
(ICT) platform, SARA-data, to monitor on real-time different source
clinical, imaging (DEXA), laboratory and physical activity data
generated at investigation sites, centralised lab and by the patients
via wearable devices and auto-evaluation questionnaires.
designed clinical trials may be inadequate for collecting informative
long-term clinical data in older adults. Rigid scheduling of visits and
investigations negatively affects compliance and retention rate while
increasing the risk of biased results. Little is known about
intercurrent changes in physical function between protocol scheduled
visits at the clinic.
A novel approach, including systematic and
continuous use of wearable devices, allows to collect and integrate in
one single web-based portal all different data sources: electronic Case
Report Form clinical data, imaging DEXA scans, biochemistry-haematology
results from a centralised laboratory and disease related biomarkers. Of
note, continuous physical activity recording is enabled during the
whole clinical trial duration by providing each older participant with a
wrist-worn accelerometer. The device transmits anonymised activity data
to SARA platform via a non-intrusive, unattended, home-centred
machine-to-machine technology. This kind of high volume data, directly
generated by the patient during several months, fulfils the definition
of Health-related Big Data, and will constitute an important resource
for additional, supportive analyses complementing standardised muscular
function assessments. These data are generated in a real-life context
and could provide answers to specific questions by regulators and
Conclusions: SARA-data is an adapted ICT, real-time
data platform for conducting long-term clinical trials in older
patients. The potential impact of using Big Data in geriatric clinical
research represents a further advantage, and enables secondary research.
CT-defined muscularity: population distribution and prognostic significance for overall survival
Dalton Luiz Schiessel1, Lisa Martin2, Michael B. Sawyer2, Oliver Bathe3, David Bigam2, Aldo Montano-Loza2, Vincent Thai2, Pierre Senesse4 and Vickie E. Baracos2
1Nutrition Department-Midwestern State University-UNICENTRO, Guarapuava, Brazil; 2University of Alberta, Edmonton, AB, Canada; 3University of Calgary, Calgary, AB, Canada; 4Institut du Cancer de Montpellier, Montpellier, France
Computed tomography (CT) is an assessment of body composition offering
high precision and specificity. In cancer patients, CT measurements of
muscularity are correlated with dose limiting toxicity, hospital length
of stay, surgery infections/complications and overall survival (OS).
Skeletal muscle compartment is one determinant of these adverse
outcomes. Small sample sets to date have hampered our ability to
understand the shape of the relationship between muscularity and
outcomes. We sought to define the sex-specific relationships between
muscularity and mortality in a large international data set including
patients from Canada and Europe.
Methods: Skeletal area (cm2) (SMA) and skeletal muscle index (SMI, cm2/m2)
were assessed by CT at the 3rd lumbar vertebra (L3) in advanced solid
tumor patients. Data were stratified into 10 equal groups (deciles), to
explore relationships to OS.
Results: Male patients (n = 2751)
were 64 (±11.5) years, tumor sites were colorectal (29.8%), other GI
(22.3%) and lung (17.4%) cancers that were mostly stage 4 (60.9%).
Median of OS was 20.7 (95% CI 19.1–22.3) months and mean SMI
49.5 ± 9.2 cm2/m2 and SMA 150.7 ± 29.27 cm2. Survival by deciles of SMI (univariate) are shown (Table 1).
SMI was continuously related to OS, with the longest OS in the most
muscular individuals. SMI was independently prognostic of OS in a model
adjusted for age, cancer site, stage & performance status (p = 0.021). Stratification on SMA gave similar results. Women (n = 1981)
have a smaller range of muscularity than men. Stratification of SMI and
SMA by deciles also showed a continuous relationship with OS. In men
and women of equal muscularity, survival in women was significantly
longer.Table 1. Patient characteristics in male sex: skeletal muscle index and median overall survival
Muscularity is continuously related to OS in male and female cancer
patients. Prior research used statistical tests to identify threshold
values of SMI associated with survival (i.e. “sarcopenia” thresholds);
this bivariate approach oversimplifies the relationship with OS.
Skeletal muscle capillary density predicts insulin sensitivity and muscle morphological adaptation in older adults
Tatiana Moro1,3, Camille.R. Brightwell1, Rachel R. Deer3, Elena Volpi2,3, Blake B. Rasmussen1,3 and Christopher S. Fry1,3
1Department of Nutrition & Metabolism, School of Health Professions, University of Texas Medical Branch, Galveston, TX, USA; 2Department of Internal Medicine/Geriatrics, University of Texas Medical Branch, Galveston, TX, USA; 3Sealy Center on Aging, University of Texas Medical Branch, Galveston, TX, USA
Aging induces a substantial decrease in muscle capillarization,
reducing the transport of nutrients, oxygen and hormones, such as
insulin, into muscle fibers. Thus, muscle capillarization could be
critical not only for muscle growth but also for glucose intolerance and
insulin resistance. It is known that physical activity can improve
muscle perfusion by increasing capillary density in young adults;
however, its role in older adults is still controversial.
of this study was to investigate the association between muscle
capillary density and indices of muscle hypertrophy and insulin
sensitivity before and after 12 weeks of progressive resistance exercise
Methods: 19 subjects (71.1 ± 4.3 years;
27.6 ± 3.2 BMI) were studied before and after 12 weeks of RET. Pre- and
post-training measurements of muscle mass, strength and OGTT were
obtained. Insulin sensitivity was assessed with Matsuda index and OGIS
index. In addition, pre and post study days also included percutaneous
biopsies from the vastus lateralis muscle. Immunohistochemical analysis
was used to quantify capillary density, myosin heavy chain (MyHC)
isoform expression and cross-sectional area (CSA).
Basal muscle capillarization was highly correlated with lean body mass,
sarcopenic index (SMI) and daily physical activity level (p < 0.05).
Muscle capillary density was also positively associated (p < 0.05)
with fiber type I frequency and fiber size (CSA). Moreover, higher basal
capillarization was positively correlated (p < 0.05) with a higher
improvement in the insulin sensitivity index and muscle fiber CSA. RET
increased muscle capillary density (p < 0.05), which was also
correlated with an increase in fiber CSA and MyHC type II fiber
Conclusions: Muscle fiber capillarization at
baseline may be a predictive factor for improving insulin sensitivity in
response to RET in older adults. Increases in muscle fiber perfusion
following RET are correlated with muscle growth.
3 days of human skeletal muscle disuse promote fatty infiltrations development
Guillaume Py1, Allan F. Pagano1, Thomas Brioche1, Coralie Arc-Chagnaud1,2, Rémi Demangel1 and Angèle Chopard1
1Université de Montpellier, INRA, UMR866 Dynamique Musculaire et Métabolisme, Montpellier, France; 2Freshage Research Group - Dept. Physiology - University of Valencia, CIBERFES, INCLIVA, Valencia, Spain
Fatty infiltrations, or intermuscular adipose tissue (IMAT), are
currently well-recognized components of muscle deconditioning. Although
IMAT is present in healthy human skeletal muscle, its increase and
accumulation are linked to muscle dysfunction. Although IMAT development
has been largely attributable to inactivity, the precise mechanisms of
its establishment are still poorly understood. Because the sedentary
lifestyle that accompanies age-related sarcopenia may favor IMAT
development, deciphering the early processes of muscle disuse is of
great importance before implementing strategies to limit IMAT
Methods: Here, we took advantage of the dry
immersion (DI) model of severe muscle inactivity to induce rapid muscle
deconditioning during a short period. Skeletal muscle biopsies were
obtained from the vastus lateralis of healthy men (n = 12; age: 32 ± 6) before and after 3 days of DI.
We showed that DI for only 3 days was able to decrease myofiber
cross-sectional areas (−10.6%). Protein expression levels of two key
markers commonly used to assess IMAT, perilipin and FAPB4 were
upregulated. We observed an increase in the C/EBPα and PPARγ protein
expression levels, indicating an increase in late adipogenic processes
leading to IMAT development. While many stem cells in the muscle
environment can adopt the capacity to differentiate into adipocytes,
fibro-adipogenic progenitors (FAPs) appear to play a major role in IMAT
development. In our study, we showed an increase in the protein
expression of PDGFRα, the specific cell surface marker of FAPs, in
response to 3 days of DI. It is well recognized that an unfavorable
muscle environment drives FAPs to ectopic adiposity and/or fibrosis.
This study is the first to emphasize that during a short period of
severe inactivity, muscle deconditioning is associated with IMAT
development. Our study also reveals that FAPs could be the main resident
muscle stem cell population implicated in ectopic adiposity development
in human skeletal muscle.
alterations in pre-frail/frail elderly women are in part secondary to
signals originating in persistently denervated muscle fibers
Vita Sonjak1,2, Madhusudanaro Vuda2, Kayla Miguez1,2, Carole Spake1, Kathryn J. Wright3, Anna Perez2, Jose A. Morais3, Tanja Taivassalo4 and RussellT Hepple5
1Department of Kinesiology and Physical Education, McGill University, Montreal, QC, Canada; 2Meakins Christie Laboratories and Research Institute of the McGill University Health Centre, Montreal, QC, Canada; 3Research Institute of the McGill University Health Centre, Montreal, QC, Canada; 4Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA; 5Department of Physical Therapy, University of Florida, Gainesville, FL, USA
Mitochondrial impairment is implicated in the age-related decline in
skeletal muscle, but whether the mitochondrion represents a therapeutic
target depends upon whether the changes in function of this organelle
are primary organelle defects or secondary responses to other changes in
the aging milieu. Whereas we recently showed that
mitochondrial function changes in octogenarian men are at least partly
secondary to muscle fiber denervation, this has not been addressed in
pre-frail/frail elderly women.
respiratory capacity by high-resolution respirometry and reactive oxygen
species (ROS) emission by Amplex Red was determined in saponin
permeablized myofibers obtained from Vastus lateralis muscle
biopsies of prefrail/frail elderly (FE; 79.6 ± 4.9y) and healthy young
inactive (YI; 23.1 ± 2.5y) women. The effect of denervation on
mitochondrial function during the ROS assay was assessed
pharmacologically upon inhibition of cPLA2 with arachadonyl trifluoromethyl ketone (AACOCF3). The presence of denervated myofibers was assessed morphologically by histochemistry.
Muscle respiratory capacity was reduced in FE due to lower
mitochondrial content, whereas FE exhibited higher ROS emission even
after normalizing for mitochondrial content compared to YI group. The
reduction in ROS production compared to ethanol vehicle control in FE
(Ethanol: 1.3 ± 0.5 pmol/min/mg vs AACOCF3: 0.8 ± 0.4 pmol/min/mg; p < 0.001)
reveals a modulating impact of denervation on mitochondrial function in
FE women, as seen previously in octogenarian men. Consistent with this,
there was a significant accumulation (15.9%) of very small fibers
(defined as a size ≤1505 μm2) exhibiting histological evidence of denervation (high non-specific esterase activity) in FE.
We can conclude that denervation plays a modulating role in skeletal
muscle mitochondrial function in prefrail/frail elderly women,
suggesting therapeutic strategies in advanced age should focus on the
causes of persistent denervation.
Relationships between the branched chain amino acid transporter LAT 3 and Myosin Heavy Chain proteins in human skeletal muscle
Britt-Marie Iresjö, Cecilia Engström and Kent Lundholm
Institute of Clinical Sciences, Dep. of Surgery, Sahlgrenska Academy, University of Gothenburg, Sweden
Recent studies indicate participation of amino acid transporter
proteins in activation of mTOR signaling and down-stream increase in
muscle protein synthesis. In a previous study we identified amino acid
transporter LAT 3, a transporter of BCAA, met, phe, as significantly
altered in response to provision of total parenteral nutrition (TPN)
(p < 0.01). Here we investigate if alterations in LAT3 mRNA and
protein concentrations reflect altered gene transcription of myosin
Methods: 22 patients (mean weight loss 6 ± 2%)
scheduled for upper GI-surgery received either a continuous standard TPN
infusion (0.16 gN kg−1 day−1, 30 kcal kg−1 day−1)
or saline infusion for 12 hours overnight before operation. Biopsies
from the rectus abdominis muscle were taken at start of operation. LAT 3
mRNA and mRNA of Myosin heavy chain (MHC) isoforms MHC1, MHC2A and
MHC2X were analyzed by real-time PCR. LAT3 transporter protein content
was quantified by western blot in a subgroup of patients (n = 18). Linear regression was used for analyses of relationships.
Results: MHC2A mRNA concentrations showed a positive regression with LAT 3 mRNA (r = 0.56; p = 0.007),
while there were no relationship between MHC1 or MHC2X and LAT3 mRNA
concentrations. There were a negative relationship between MHC2A mRNA
and LAT 3 protein content (r = 0.62; p = 0.007) while MHC2X mRNA showed a positive linear relationship with LAT3 protein content (r = 0.53; p = 0.02). No relationship was found between MHC1 mRNA and LAT3 protein content.
Both mRNA and protein concentrations of the branched chain amino acid
transporter LAT 3 showed a significant relationship with Myosin Heavy
Chain 2A mRNA concentrations in muscle cells. The lack of relationship
with other Myosin Heavy chain isoforms and LAT3 may suggest specific
regulation of individual MHC transcripts. These findings deserve further
nutritional evaluations to understand the control of myofibrillar
content and mtDNA deletion mutation abundance in skeletal muscle of
sedentary high- and low-functioning elderly individuals
Anna Picca1, Andres Gordillo Villegas2, Robert Mankowski2, Angela Maria Serena Lezza3, Riccardo Calvani1, Emanuele Marzetti1, Roberto Bernabei1 and Christiaan Leeuwenburgh2
of Geriatrics, Neurosciences and Orthopedics, Catholic University of
the Sacred Heart School of Medicine, Teaching Hospital “Agostino
Gemelli”, Rome, Italy; 2Department of Aging and
Geriatric Research, Institute on Aging, Division of Biology of Aging,
University of Florida, Gainesville, FL, USA; 3Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy
Mitochondrial dysfunction in skeletal myocytes has been proposed as a
major factor contributing to the development and progression of
sarcopenia. Hence, the quantitation of mitochondrial DNA (mtDNA)
abundance and mtDNA deletion mutation load may help clarify the role of
mtDNA instability in muscle aging.
Methods: We applied
real-time PCR-based approaches to total DNA purified in muscle samples
obtained from young adults, sedentary older adults, classified as high-
and low-functioning based on the Short Physical Performance Battery
(SPPB), in order to examine the effect of aging on key quantitative
alterations of mtDNA and how this relates to physical performance.
Muscle volume, as quantified via 3D-NMR, was decreased by 38% and 30%
in low- (LFE) and high-functioning elderly (LFE) participants,
respectively, when compared to young and high-functioning elderly
participants, respectively, and positively correlated with physical
performance. The content of mtDNA was found to be significantly reduced
in both groups of elderly participants, regardless of the SPPB score,
relative to their younger counterparts. The age-associated decrease in
mtDNA abundance was paralleled by an increase in the mtDNA deletion in
HFE and LFE participants, with no differences between the two groups.
Further investigations will probe alterations in mtDNA encoding genes:
NADH dehydrogenase 1 (ND1/Complex 1), Cytochrome b (Complex III), and
cytochrome c oxidase (COI/Complex IV).
study shows altered mitochondrial homeostasis in muscles of aged human.
The decline in myocyte mitochondrial mass and the accumulation of mtDNA
deletions may therefore represent critical steps to muscle aging and
possible targets for interventions against sarcopenia.
Genetic variants associated with physical performance and anthropometry in old age: a genome-wide association study in the ilSIRENTE cohort
Emanuele Marzetti1, David Heckerman2, Bryan J. Traynor3, Anna Picca1, Riccardo Calvani1, Dena Hernandez4, Michael Nalls5, Sampath Arepali4, Luigi Ferrucci6, Roberto Bernabei1 and Francesco Landi1
for Geriatric Medicine (CEMI), Department of Geriatrics, Neurosciences
and Orthopedics, Catholic University of Sacred Heart, Rome, Italy; 2Microsoft Research, Los Angeles, CA, USA; 3Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; 4Genomics Technology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; 5Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; 6Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA
Unraveling the complexity of aging is crucial for understanding its
mechanisms and why aging is the risk factor for most chronic conditions.
The advancements marked by genome-wide association studies (GWASs) have
sparked interest in gene cataloguing in the context of aging and
age-related conditions. Here, we used GWAS to explore whether single
nucleotide polymorphisms (SNPs) were associated with functional and
anthropometric parameters in a cohort of old community-dwellers enrolled
in the ilSIRENTE aging study.
Methods: Analyses were carried out in men and women aged 80+ years enrolled in the ilSIRENTE Study (n = 286) and replicated in the inCHIANTI Study (n = 1055). Genotyping was accomplished on Infinium Human610-QUAD version 1.
Results: In the ilSIRENTE
population, genetic variants in ZNF295 and C2CD2 (rs928874 and
rs1788355) on chromosome 21q22.3 were significantly associated with the
4-meter gait speed (rs928874, p = 5.61 × 10−8; rs1788355, p = 5.73 × 10−8). This association was not replicated in the inCHIANTI population.
Our findings suggest that specific SNPs may be associated with a key
measure of physical performance in older adults. GWASs using larger
samples are needed to confirm these preliminary results to enhance our
comprehension of complex age-associated phenomena.
muscle dysfunction in cancer-associated cachexia characterized by
changes in proliferation and differentiation markers in gastrointestinal
Gabriela Salim de Castro1, Joanna Darck Carola Correia Lima1, Estefanía Simões Fernández1, Raquel Galvão Figueredo1, Emídio Marques de Matos-Neto1, Paulo Sérgio Alcantara Martins2, José Pinhata Otoch2,3, Athanassia Sotiropoulos4, Dario Coletti5 and Marília Cerqueira Leite Seelaender1,3
1Cancer Metabolism Research Group, University of São Paulo, Brazil; 2Department of Clinical Surgery, University Hospital, University of São Paulo, Brazil; 3Faculdade de Medicina, University of São Paulo, Brazil; 4Inserm U1016, Institut Cochin, France; 5Department of Biological Adaptation and Ageing B2A, Pierre et Marie Curie University (Paris 6), France
Cancer-associated cachexia is a metabolic syndrome characterized by
weight loss and systemic inflammation. Exacerbated inflammation seems to
cause protein and energy disorders leading to reduced survival and
quality of life. Furthermore, systemic inflammation may be involved in
muscle wasting and impaired myogenesis. Therefore, the present study
aimed to evaluate satellite cells markers and cell signaling proteins in
skeletal muscle of gastrointestinal cancer patients.
Methods: Patients with gastrointestinal cancer were recruited after signature of the informed consent form. Rectus abdominis
muscle biopsies were collected in surgery. Patients were separated into
Weight-Stable Cancer (WSC) and Cachectic Cancer (CC) groups (WSC n = 13 and CC n = 16) according to criteria described by Evans et al. (2008). Muscle mRNA was extracted and real-time PCR gene expression was analysed using 2-ΔΔCT. Cell signalling proteins and CX3CL1 were quantified with Luminex®xMAP technology.
mRNA relative levels of two transcription factors expressed mainly by
satellite cells, PAX7 and MYF5, were increased in CC patients (p = 0.004 and p = 0.003 respectively). Furthermore, CC muscle biopsies showed decreased JNK (p = 0.006) and p53 protein content (p = 0.03) and an increase in those of ATF-2 (p < 0.03), cJUN (p = 0.04) and mitogen- and stress-activated protein kinase (MSK1) (p = 0.038)
in relation to WSC patients. CX3CL1, a chemokine that may be involved
in muscle regeneration, was decreased in CC patients (p = 0.0004).
Changes in satellite cells markers seems to indicate an attempt towards
myoblasts proliferation and differentiation; however, this process may
be compromised as suggested by the lower p53 protein content. Sustained
systemic inflammation may impair myocyte differentiation and
consequently decrease muscle regeneration capability in CC patients.
Further analysis of muscle differentiation markers are required to
corroborate these findings.
Evaluation of serum markers for assessing muscle mass in cancer cachexia
Christina Van Der Borch1, Sara Wing1, Rachel Murphy2, Ami Grunbaum3, Sean Eintracht3, Elizabeth MacNamara3, Vickie Baracos2, Vera Mazurak2 and R. Thomas Jagoe1
1McGill Cancer Nutrition Rehabilitation Program Clinic, Jewish General Hospital, Montreal, Canada; 2Alberta Institute for Human Nutrition, University of Alberta, Edmonton, AB, Canada; 3Department of Clinical Biochemistry, Jewish General Hospital, Montreal, Canada
Low muscle mass is a defining feature of cancer cachexia. Methods for
measuring muscle mass exist, but these are often too time-consuming and
expensive for the routine evaluation of patients in clinic. Several
different circulating markers of muscle mass have been proposed but to
date, none have been validated.
measurements of body composition (CT cross-sectional imaging or DEXA)
were performed and simultaneous blood samples were collected, on up to 4
occasions, from patients with cancer. Serum assays for nine different
candidate markers of muscle mass were measured. The correlation between
each serum marker and muscularity (appendicular skeletal muscle mass
index (ASMI (kg/h2)) was assessed. In addition, comparison of values of each serum marker in those with and without low muscle mass was performed.
43 patients (67% men), mean (SD) age 62(12) yr were recruited at two
sites. 60% had lung cancer and 91% had advanced (stage III/IV) disease.
Serum levels of Creatinine Kinase, Myoglobin, Ghrelin, Testosterone
(men), Insulin, Growth Hormone, Cortisol and C-reactive protein did not
correlate with ASMI. However, insulin-like growth factor-1 (IGF) levels
did correlate with ASMI (e.g. visit 1: R = 0.38, P = 0.02).
Furthermore, using sex-specific cut-offs for ASMI, IGF levels was the
only marker which was significantly different in sarcopenic individuals
(Sarcopenia N vs Y: 24.9 vs 17.3 nmol/l, P = 0.04). Lower IGF
levels were also associated with greater loss of muscle mass (e.g.
IGF < 17 nmol/l: 0.8 kg loss vs 0.2 kg gain, P = 0.02).
Of the serum markers tested, only IGF appears to be useful to identify
advanced cancer patients who have low muscle mass. Furthermore, low
circulating IGF may also help predict which patients are most at risk of
further muscle loss.
TNF-α-mediated inflammatory apoptosis and angiogenesis in physical inactivity-induced muscle atrophy
Xiangke Chen1, Chen Zheng2 and Joseph Shiu Kwong Kwan1
1Department of Medicine, The University of Hong Kong, Hong Kong; 2Department of Sports Science and Physical Education, The Chinese University of Hong Kong, Hong Kong
Skeletal muscle atrophy can result from physical inactivity, space
flight and chronic bed rest associated with ageing. Hind-limb unloading
(HU) is an accepted rodent model of muscle disuse to simulate physical
inactivity. We investigated the roles of tumor necrosis factor-alpha
(TNF-α) in apoptosis and angiogenesis pathways using HU-induced muscle
Methods: HU was performed in 8-week-old ICR
mice for 14 consecutive days. We compared muscle mass, muscle strength,
morphology, and blood flow, reactive oxygen species (ROS), TNF-α,
vascular endothelial growth factor (VEGF), endothelial NOS (eNOS),
cytochrome C (Cyto-C), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X
protein (Bax), caspase-9, and caspase-3 between HU vs. control mice.
Results: As compared to control mice, HU mice were significantly lower in muscle mass and strength (p < 0.01),
with their muscle fibers arranged more loosely along a different
direction. HU mice had significantly higher levels of blood ROS,
expressions of TNF-α, VEGF, and caspase-3 in the skeletal muscle (p < 0.01), and the blood flows in the hind-limb and whole body were significantly higher (P < 0.05).
No significant differences were found in the expressions of other
biomarkers between the two groups. TNF-α was highly correlated with both
caspase 3 (r = 0.725, P < 0.01) and VEGF (r = 0.725, P < 0.01) in the hind-limb muscles in response to HU.
TNF-α is involved in both the caspase 3-mediated apoptosis pathway and
the VEGF-mediated angiogenesis pathway in HU-induced muscle atrophy.
Development of future treatments for physical inactivity-induced muscle
atrophy should take into consideration the findings of this study.
5-Fluoroucil's effect on indices of skeletal muscle wasting in ApcMin/+ mice
Brittany R. Counts1" noteRef="jcsm12255-subcmp-0072-note-0001, Kristen M. Larsen2" noteRef="jcsm12255-subcmp-0072-note-0001, Brandon N. VanderVeen1, Justin P. Hardee1, Dennis A. Fix1, Maydelis K. Minaya2, Celestia Davis2,3, Maria M. Peña2,3 and James A. Carson1,3
1Arnold School of Public Health, University of South Carolina, Columbia, USA; 2Department of Biological Sciences, University of South Carolina, Columbia, USA; 3Center for Colon Cancer Research, University of South Carolina, Columbia, USA
†Denotes co-first authors.
Although colon cancer has the second highest cancer mortality rate,
targeted treatments are improving survival. 5-Fluoroucil (5-FU) is a
common chemotherapeutic used to treat colon cancer. Cancer therapy can
adversely affect many tissues and processes including skeletal muscle.
However, 5-FU's effects on skeletal muscle quality and function are not
Purpose: Therefore, we examined the effect of a 5-FU
treatment regime on indices of skeletal muscle wasting in a
pre-clinical model of colon cancer.
Methods: At 12 weeks of age, after intestinal and colon polyp development, male ApcMin/+ mice were treated with PBS (n = 10)
or 5-FU (n = 10) once every two weeks for six weeks. At 18 weeks of age
muscles were examined for inflammation, protein turnover, and
mitochondrial signaling associated with wasting.
Both PBS (−6 ± 2%) and 5-FU (−4 ± 1%) mice lost bodyweight and were
initiating cachexia. Absolute grip strength and triceps surae muscle
mass were higher with 5-FU treatment. Muscle inflammatory signaling
(p-STAT, p-65) was suppressed by 5-FU. Protein turnover regulation was
improved by 5-FU (increased p70S6K, decreased Atrogin-1), and 5-FU also
increased quadriceps muscle ribosomal capacity. Additionally, 5-FU
treatment rescued muscle metabolic signaling associated with AMPK,
DRP-1, and PGC-1α. Autophagy-related signaling (LCB II: I, BNIP3, p62)
was decreased by 5-FU.
Discussion: Collectively, we report
that the 5-FU treatment to tumor bearing mice improved indices of muscle
quality related to the wasting phenotype. Future studies will need to
delineate the potential mechanisms regulating 5-FU's protective effects
on muscle metabolic and functional capacities independent to
cancer-induced body weight loss.
Acknowledgements: Supported by NCI R01-CA121249 and NIGMS 5P30GM103336.
nucleotide-mediated enhancement of mitochondrial density and
bioenergetics improves skeletal muscle wasting phenotypes via an
Cara A. Timpani1,2, Craig A. Goodman1,2,3, Christos G. Stathis1,2,3, Alan Hayes1,2,3 and Emma Rybalka1,2,3
1College of Health & Biomedicine, Victoria University, Melbourne, Australia; 2Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, Australia; 3Institute of Sport, Exercise & Active Living (ISEAL), Victoria University, Melbourne, Australia
In the fatal X-linked skeletal muscle wasting disease, Duchenne
Muscular Dystrophy (DMD), the progressive degeneration of skeletal
muscle coincides with impaired mitochondrial function, alterations in
structural networking, the inability to respond to metabolic stress
signaling and the decline of cellular energy stores. Similar metabolic signatures are observed in other skeletal muscle wasting phenotypes such as cachexia, diabetic myopathy, chronic obstructive pulmonary disease and sarcopenia.
We have investigated whether the purine nucleotide, adenylosuccinic
acid (ASA), a mitochondrial and purine nucleotide cycle stimulant, can
be used to enhance mitochondrial dynamics, cellular bioenergetics and
attenuate skeletal muscle wasting in the mdx mouse model of DMD.
Methods: Four-week-old control (C57Bl/10; CON) and dystrophic mdx mice were treated with 3000 μg·mL−1 ASA in drinking water (~350 mg·kg−1 day−1) for 8 weeks. Skeletal muscle mitochondrial density, viability, oxidative function and superoxide (O2−)
content, alongside metabolic stress response signaling (adenosine
monophosphate protein-activated kinase (AMPK) and peroxisome
proliferator-activated receptor gamma coactivator-1α/β (PGC1α/β) and
histopathology, including fiber cross-sectional area,
damage/regeneration, pseudohypertrophy and fat and fibrotic tissue
infiltration, were assessed.
Results: ASA treatment increased mitochondrial density (by >200% in isolated flexor digitorum brevis (FDB) fibers (p < 0.01) and ~50% in tibialis anterior (TA) cross-sections (p < 0.0001) and viability (by ~20% in FDB fibers; p < 0.05),
as well as the bioenergetical profile of TA muscles, including
phosphocreatine (p < 0.01) concentration. ASA also reduced O2− production by ~25% (p < 0.05). These changes were independent of AMPK and PGC1α/β activation in mdx
quadriceps. ASA treatment significantly attenuated skeletal muscle
damage (p < 0.01) and wasting (p < 0.05) in mdx
TA, as well as downstream histopathological features including
pseudohypertrophy (p < 0.05), centronucleated fibers (p < 0.01),
lipid accumulation (p < 0.05) and connective tissue infiltrate (p < 0.001).
Our data highlight a protective effect of ASA on skeletal
muscle-wasting phenotypes by stimulating unknown molecular pathways to
enhance mitochondrial density and viability, as well as cellular
- 1Med Hypoth; 2015 et al.,
- 2J Cachexia Sarcopenia Muscle; 2013 4(2):145–155. et al.,
- 3J Nutrition Metabolism, 2012,
- 4J Thorac Dis, 2015 7(10): E418-E438. et al.,
- 5Biogerentology, 2014 15(3): 214–232. et al.,
Chronic tobacco smoke exposure induces aryl hydrocarbon receptor-dependent neuromuscular junction degeneration
Kayla Miguez1, Madhusudanarao Vuda2, Vita Sonjak1, Daren Elkrief1, Yana Konokhova3, Anna Perez2, Angela Rico de Souza2, Carolyn J. Baglole2 and Russell T. Hepple3
1Department of Kinesiology & Physical Education, McGill University, Montreal, QC, Canada; 2Meakins Christie Laboratories and Research Institute of the McGill University Health Centre, Montreal, QC, Canada; 3Department of Physical Therapy, College of Health & Health Professions, University of Florida, Gainesville, FL, USA
Chronic tobacco smoke (TS)-related diseases, such as cancer,
cardiovascular disease and Chronic Obstructive Pulmonary Disease, are
associated with common elements of skeletal muscle deterioration (fast
fiber shift, erosion of oxidative capacity and atrophy) that worsen
clinical outcomes, including increasing the risk of death. Although
chronic TS exposure is an exacerbating factor in conditions involving
neuromuscular junction degeneration, including aging and amyotrophic
lateral sclerosis (ALS), there are as of yet no data addressing the
impact of chronic TS exposure on the neuromuscular junction and how this
relates to the muscle alterations induced by TS. Furthermore, although
chronic activation of the aryl hydrocarbon receptor (AHR) is linked to
neurotoxicity, and the AHR responds to multiple compounds in TS, no
studies have considered the role of the AHR in mediating the adverse
impact of chronic TS exposure on muscle.
Methods: In the
first set of experiments, we exposed 8-month-old C57Bl6 male mice to
60 minutes of TS exposure twice daily, 5 days per week, for 16 weeks.
Following the final TS exposure, we examined muscle mass, neuromuscular
junction morphology by confocal microscopy, and oxidative capacity by
high-resolution respirometry. In the second set of experiments, we
determined whether whole body knockout of the AHR would attenuate the
neuromuscular junction impact of 8 weeks of TS exposure in 3-month-old
Results: 16 weeks of TS induced mild atrophy of
limb muscle that was associated with neuromuscular junction degeneration
and mild erosion of oxidative capacity. Strikingly, AHR knockout
completely prevented the TS-induced neuromuscular junction degeneration
and reduced indices of stress in homogenates of spinal cord tissue.
Chronic TS exposure induces neuromuscular junction degeneration that is
dependent upon the AHR, providing novel insights into the mechanisms by
which chronic TS adversely impacts skeletal muscle.
of beneficial effects of beta-hydroxy-beta-methylbutyrate (HMB)
supplementation during inactivity: from physical parameters to molecular
Thomas Brioche, Rémi Roumanille, Allan F. Pagano, Angèle Chopard and Guillaume Py
Université de Montpellier, INRA, UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France
Inactivity is the main factor during aging leading to physical
alterations, such as muscle atrophy, strength reduction, balance and
coordination impairment, and aerobic fitness decrease. Muscle atrophy
and strength decrease can be explained by an impairment of muscle
protein balance characterized by a decreased protein synthesis and an
increased proteolysis. Also, a decrease in mitochondria content and
functions are involved in the impairment of aerobic fitness observed
during aging. These mechanisms are affected by numerous upstream factors
including a decrease in the release of anabolic hormones, increased
pro-inflammatory cytokines production and an increase in muscle
oxidative stress. Each of these adaptations could turn to serious health
deterioration during aging. Beta-hydroxy-beta-methylbutyrate (HMB), a
leucine metabolite, has been described in normal condition to increase
aerobic fitness and prevents muscle atrophy during cancer through
enhanced mitochondria functions, anti-catabolic and anabolic mechanisms.
We hypothesized that HMB could be used as a nutritional countermeasure
to prevent physical deconditioning due to inactivity.
Mature C56Black6J male mice were hindlimb-unloaded (HU) or kept
ambulatory for 14 days. Mice were provided either HMB (250 mg/kg body
mass per day) or distilled water by oral gavage for 21 days. Aerobic
fitness was evaluated and a multiple static rod test assessed
coordination and balance. Histological and molecular analyses were done
on soleus muscle and plasma.
Results and Discussion: HMB
treatment counteracted soleus slow and fast-twitch fibers atrophy.
Aerobic fitness, coordination and balance were also counteracted in HU
treated mice. These results can be explained by a better protein balance
in treated mice compared to placebo mice as shown by higher protein
synthesis and lower proteolysis in mice receiving HMB. According to our
results, lower oxidative stress and inflammation could explain the
better protein balance in treated mice.
Conclusions: HMB could thus be envisaged as an efficient nutritional countermeasure.
Our work is supported by grants from the French “Centre National d'Etudes Spatiales” (CNES).
Overexpression of G6PD delays the onset of frailty in mice acting on muscle mass and metabolism
Coralie Arc-Chagnaud1,2, Andrea Salvador-Pascual1, Thomas Brioche2, Angèle Chopard2, Guillaume Py2, Mari Carmen Gomez-Cabrera1 and José Viña1
1Freshage Research Group - Dept. Physiology - University of Valencia, CIBERFES, INCLIVA, Valencia, Spain; 2University of Montpellier, INRA, UMR866, Dynamique Musculaire et Métabolisme, Montpellier, France
Frailty is a clinical syndrome associated with the aging process, which
leads to a decreased physical function. The damages induced by reactive
oxygen species (ROS) in cells accentuate this process. The antioxidant
system is largely based on the reducing power of NADPH, whose levels are
mainly determined by the enzyme glucose-6-phosphate dehydrogenase
Material and methods: Using a specific model of
Tg-mice overexpressing G6PD, we measured oxidative stress parameters,
cross-sectionnal area (CSA) of muscle fibers, markers regulating protein
synthesis, mitochondrial dynamics and apoptosis. We used a cohort of WT
and G6PD-Tg old female mice (from 18 to 26 months old) to evaluate the
evolution of 5 functional parameters and establish a score for frailty
based on the construct described by Linda Fried. CSA and molecular
markers were measured on 21 months old mice.
results relative to functional test demonstrated that 18–20 and
23–24 months old G6PD-Tg animals performed better in the motor
coordination test than the WT. At the age of 23–24 months, 45% of
WT-mice were considered frail for maximal strength vs 4.8% in the
G6PD-Tg group. Taking into account the 5 different parameters, we
founded that the percentage of mice considered as frail is higher in the
WT than in the G6PD-Tg group. G6PD-Tg mice exhibited higher muscle
fiber CSA, levels of reduced glutathione (GSH), lower levels of
apoptosis and our results suggest a higher protein synthesis in muscle
Conclusions: Finally, overexpression of G6PD in
mice prevents frailty in 18 to 26 months old mice acting on muscle mass
and metabolism (protein balance, oxidative stress, mitochondria and
muscle alterations in an obese rat model of heart failure with
preserved ejection fraction (HFpEF) are not reversed by exercise
T. Scott Bowen1, Christian Herz1, Natale P.L. Rolim2, Gustavo di Silva2, Ulrik Wisloff2 and Volker Adams1
1Department of Internal Medicine and Cardiology, Leipzig University-Heart Center, Leipzig, Germany; 2K.G.
Jebsen Center of Exercise in Medicine, Department of Circulation and
Medical Imaging, Faculty of Medicine, Norwegian University of Science
and Technology, Trondheim, Norway
Despite normal left ventricular ejection fraction (LVEF), patients with
heart failure and preserved left ventricular ejection fraction (HFpEF)
present exercise intolerance which can be attenuated by exercise
training. Alterations in skeletal muscle have been described in HFpEF,
yet the underlying mechanisms involved as well potential benefits
mediated by exercise training remain unknown. The present study,
therefore, used a cardiometabolic rat model of HFpEF to further
elucidate: 1) the skeletal muscle alterations induced; and 2) the
effects of aerobic exercise training during secondary prevention.
Methods: After 20 weeks, obese Zucker diabetic fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats (n = 12) were compared to their lean counterparts (n = 8), with a further 3 groups of obese ZSF1 rats assessed 8 weeks later following sedentary behavior (n = 15), moderate-continuous training (MCT; n = 11) or high-intensity interval training (HIIT; n = 11) on a treadmill.
Results: Obese rats evidenced HFpEF: diastolic dysfunction, LV hypertrophy, and exercise intolerance were present (P < 0.05)
with LVEF preserved. HFpEF rats demonstrated ~20% reduction
(P < 0.05) in both fiber cross-sectional area and capillary-to-fiber
ratio in the extensor digitorum longus (EDL) skeletal muscle, which were
not reversed by exercise training. These alterations were further
associated with a reduction in absolute maximal force by ~30% and
greater fatigability by ~20% in all HFpEF groups compared to controls.
A cardiometabolic obese rat model of HFpEF was associated with skeletal
muscle atrophy, impaired capillarity, and functional deficits, yet
these alterations could not be reversed by aerobic exercise training.
Whether these findings translate to patients, whereby exercise training
has limited efficacy in treating skeletal muscle impairments in HFpEF,
requires further investigation.
Inhibition of TGF-β pathway protects diaphragm from both muscle atrophy and weakness during chronic sepsis
Baptiste Jude1, Florine Tissier1, Mickael Droguet1, Karelle Léon1, Marie-Agnès Giroux-Metges1,2 and Jean-Pierre Pennec1
1EA 4324 ORPHY, IBSAM, UFR Médecine et Sciences de la Santé, Université de Bretagne Occidentale, Brest, France; 2Explorations Fonctionnelles Respiratoires, CHRU de Brest, Brest, France
Diaphragm weakness is a risk factor leading to prolonged mechanical
ventilation, increased morbidity and death for patients in intensive
care units. Muscle dysfunction is related to an unbalance between
protein synthesis and breakdown. Glucocorticoids and pro-inflammatory
cytokines such as TNF-α and IL-6 play an important role in the
activation of calpain and ubiquitin proteasome system. Since few years,
myostatine, a member of TGF-β family, seems to strongly trigger
activation of protein breakdown. The aim of this study was to
investigate the potent benefit effect of a TGF- β receptor inhibitor in
muscle function during chronic sepsis.
sepsis was induced by cecal ligation and puncture (CLP) and carried out
during 7 days. Three groups were realized: sham group, septic group, and
septic group with daily intra peritoneal injection of TGF-βRI inhibitor
(LY364947 at 1 mg/kg) starting 24 h after sepsis induction (LY group).
Rats were sacrificed 7 days after sepsis induction, and the diaphragm
was removed for muscle contraction recordings then weighted. Mean values
are compared to sham group.
Results: Chronic sepsis led to
a significant decrease of 20% of diaphragm mass (176.7 ± 15 g vs.
221.1 ± 12.4 g in sham group) but with inhibitor treatment, the mass was
not significantly modified (218.1 ± 20.8 g). Concerning muscle
contraction, absolute force was decreased in septic group by
approximatively 35% (75 ± 16 g vs. 115.4 ± 9 g in sham group), and in LY
group the maximal force was restored to 109.7 ± 8 g. In the same
manner, the specific force was decreased by 32% in septic group
(92.3 ± 21 g/cm2 vs. 135.2 ± 8 g/cm2 in sham group) whereas there was no difference in LY group (140.7 ± 10 g/cm2).
This work demonstrates that the inhibition of TGF-β pathway can protect
muscle such as diaphragm from weakness and proteolysis during chronic
sepsis. This could be of a major importance in the care of septic
of β hydroxy-β-methylbutyrate on liver regeneration, skeletal muscle
protein balance, and amino acid concentrations in partially
Milan Holeček and Melita Vodeničarovova
Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic
Beta-hydroxy-beta-methylbutyrate (HMB) is a leucine metabolite used as a
nutritional supplement for preservation of muscle mass in elderly and
muscle wasting disorders, and as an ergogenic aid in exercise. Although
most of the HMB is produced in the liver, there are no reports of the
effects of HMB in subjects with liver injury. We examined the effects of
HMB on liver regeneration, muscle protein balance, and amino acid
concentrations in rats after partial (68%) hepatectomy (PH).
HMB (200 mg/kg/day) or saline were administered using osmotic pumps to
PH or laparotomized rats for 7 days. The animals were then sacrificed by
exsanguination and the liver, m. soleus (SOL, slow-twitch, red muscle),
and m. extensor digitorum longus (EDL, fast-twitch, white muscle) were
quickly removed and weighed. Blood plasma and tissue samples were kept
in −80 °C until analyses. ANOVA and Bonferroni multiple comparisons
procedure were used for statistical analysis of the results.
In PH animals we found lower concentrations of glucose, triglycerides
and urea, and higher concentrations of creatinine, bilirubin, alanine,
and ketoisovalerate in blood plasma, lower weights and protein contents
in EDL, and lower weights and protein and DNA contents in the liver when
compared with laparotomized animals. In PH rats treated by HMB we found
higher concentrations of urea, triglycerides, branched-chain amino
acids (BCAA; valine, leucine, isoleucine) and branched-chain keto acids,
and lower concentrations of glucose and creatinine in blood plasma,
higher BCAA concentrations in muscles and in the liver, and higher DNA
contents in the liver than in saline treated animals. The effect of PH
on muscle weights and protein contents was in HMB treated rats
Conclusions: The results indicate that HMB
administration affects metabolism of the BCAA and has favourable effects
on protein balance in muscles and liver regeneration in PH animals.
Metabolic reprogramming in order to polarize macrophages and to sustain skeletal muscle regeneration
Stefania Gorini1†, Laura Vitiello1†, Maurizia Caruso2, Francesca De Santa2, Giuseppe Rosano1,3 and Elisabetta Ferraro1
1Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, Rome, Italy; 2Institute of Cell Biology and Neurobiology (IBCN), National Research Council of Italy (CNR), Rome, Italy; 3Cardiovascular and Cell Sciences Institute, St George's University, London, UK
†These authors have equally contributed to this work
Macrophages play different roles in tissue homeostasis, as they are
involved in defense from pathogens, debris removal as well as in tissue
repair. Their effects are related to their activation/polarization
state, which depends on the stimuli they receive. Two major MF phenotype
can be distinguished; M1, a proinflammatory phenotype, and M2, a
pro-tolerogenic and tissue repair-favoring profile.
regenerating skeletal muscle, M1 inhibit myogenic precursor cell fusion
while M2 promote satellite cell differentiation to form mature myotubes.
It has been demonstrated in vivo—included in humans—that
macrophages sequentially orchestrate adult myogenesis during
regeneration of damaged skeletal muscle where differentiating
myogenin-positive myogenic precursor cells preferentially couple to
Interestingly, the activation and
polarization of macrophages is associated to a well-defined metabolic
reprogramming and a robust association between the metabolic state and
the phenotype of macrophages exists. In particular, M1 obtains energy
mainly by glycolysis while M2 relies mostly on the oxidative metabolism.
Several drugs, defined metabolic modulators, have been extensively
studied in cardiology and their ability to reprogram the metabolism of
the myocardium and to optimize the production of energy has been
Methods: Here, we treated un-stimulated and M2-stimulated macrophages with metabolic modulators, in vitro.
Moreover, we administered trimetazidine (TMZ), an MM also used in
clinical practice, to mice recovering from skeletal muscle damage due to
Results: We showed that metabolic modulators
are capable to enhance M2 polarization in vitro, inducing the expression
of M2-related genes both in M2-stimulated macrophages and in
un-stimulated macrophages. We also observed that in injured muscle of
TMZ treated mice there is a decrease in the number of muscle
Conclusions: Taken together,
these preliminary data suggest that metabolic modulators can be used to
modulate macrophage polarization, which might be useful to sustain
Skeletal muscle function might be affected by Mineralocorticoid Receptor activation.
Alessandra Feraco1, Francesca Molinari1, Massimiliano Caprio2, Andrea Armani2, Elisabetta Ferraro2 and Giuseppe Rosano1,3
1Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, Rome, Italy; 2Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy; 3Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London, UK
Background and aims:
Mineralocorticoid Receptor (MR) modulation affects adipocyte function,
and MR antagonism has been shown to improve glucose metabolism in a
mouse model of diet-induced obesity. Moreover, there is evidence that MR
inhibition affects insulin signaling pathway in skeletal muscle. Here,
we aim at elucidating the role of MR in regulating skeletal muscle
Methods: We analysed MR activation in a murine
myoblast cell line (C2C12), and in parallel, we characterized the
impact of MR activation on signaling pathways involved in skeletal
muscle metabolism in obese mice.
Results: We observed an increase in MR protein expression in C2C12 myotubes during differentiation in vitro.
Treatment of myotubes with aldosterone induced an increase in
serum/glucocorticoid-regulated kinase1 (SGK1) protein phosphorylation.
In addition, aldosterone increased activation of AMP-activated protein kinase (AMPK), a key regulator of muscle metabolism, and Acetyl-CoA carboxylase (ACC),
a downstream target of AMPK signaling. Importantly, spironolactone was
able to revert these effects, suggesting that MR affects muscle fibers
We also evaluated gastrocnemius expression of
MR and metabolic profile in ob/ob mice. Reduction in glucose transporter
type 4 (GLUT4), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha
(PGC1 alpha) and mitochondrial transcription factor A (mtTFA) protein
levels in skeletal muscle of obese mice suggested the occurrence of
metabolic alterations in glucose uptake and mitochondrial function.
Surprisingly, SGK1 and AMPK protein phosphorylation were reduced in
obese mice, thus indicating downregulation of MR activity. This
hypothesis was confirmed by real-time qPCR, which revealed a reduction
in MR and SGK1 mRNA levels in obese mice gastrocnemius.
Our data indicate a downregulation of MR activity in skeletal muscle of
obese mice concomitant with impaired muscle metabolism and suggest a
causal role of reduced MR activity in metabolic alterations of skeletal
muscle fibers in obesity.
Genes differentially expressed during reversion of androgen-dependent skeletal muscle atrophy
Flavia A. Guarnier1†, Priscila de O. Coelho2†, Leonardo Bruno Figueiredo3, Livia S. Zaramela2, Rosely O. Godinho3 and Marcelo D. Gomes2
1Laboratory of Pathophysiology and Muscle Adaptation, State University of Londrina, Brazil; 2Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Brazil; 3Department of Pharmacology, Escola Paulista de Medicina, Federal University of Sao Paulo, São Paulo, Brazil
†Equal contributed first author
wasting or atrophy is a condition associated with major human systemic
diseases including, diabetes, cancer, and kidney failure, among others.
There is accumulating evidence from comparison of transcriptional
profiles that a common set of genes, termed atrogenes, are modulated in
atrophyi ng muscles. However, the transcriptional changes that trigger
reversion or attenuation of muscle atrophy have not been characterized
at the molecular level. To identify key factors involved in the recovery
of skeletal muscle mass, we have used cDNA microarrays to investigate
genes differentially expressed during the atrophy reversion of the
androgen-sensitive levator ani muscle (LA), in the well-established
model of castration and testosterone replacement. The data obtained in
microarray assay showed that 310 genes were differentially expressed in
LA muscles 24 hours after hormone replacement. The statistical analysis
of the p value allowed the selection of some targets to be validated
through qPCR. As expected, most of them behave as atrogenes and
responded to castration-induced atrophy. Strikingly, 7 genes (APLN,
DUSP5, IGF1, PIK3IP, KLHL38, PI15, and MKL1) did not respond to
castration but exclusively to the hormone replacement. We therefore
proposed to name these genes antiatrogens. Considering that almost all
proteins encoded by these genes may function as regulators modulators of
cell proliferation/growth, our results open new perspectives in
signaling pathway on atrophy-related syndromes field, bringing to light
also a new perspective for therapeutic approaches.
In vitro assessment of postnatal myonuclear accretion
Anita E.M. Kneppers1, Lex B. Verdijk2, Chiel C. de Theije1, Luc J.C. van Loon2, Annemie M.W.J. Schols1 and Ramon C.J. Langen1
1Departments of Respiratory Medicine; 2Human
Biology and Movement Sciences; NUTRIM School of Nutrition and
Translational Research in Metabolism, Maastricht University Medical
Centre, Maastricht, the Netherlands
Postnatal myogenesis is essential for skeletal muscle regeneration and
relies on satellite cell proliferation, differentiation and subsequent
fusion with muscle fibers (i.e., myonuclear accretion). Ex vivo,
myogenesis is primarily studied using the formation of syncytia during
myoblast differentiation, which represents aspects of developmental
myogenesis, but may incompletely portray postnatal myogenesis. We aimed
to develop an in vitro model that better reflects postnatal
myonuclear accretion (PNMA) and evaluated the effects of known
modulators of muscle plasticity.
Methods: Mononuclear C2C12
myoblasts were added to differentiated myotubes and co-cultured for
3 days. Postnatal myonuclear accretion (PNMA) was assessed by live cell
time-lapse imaging, and cell tracing by cell labelling with Vybrant® DiD
and DiO. Furthermore, a Cre/LoxP-based cell system was developed to
quantitatively assess PNMA, by the conditional expression of luciferase
upon myoblast–myotube fusion, which was detected using luminometry.
Results: Live cell time-lapse imaging, staining-based cell tracing, and recombination-dependent luciferase activity, revealed PNMA in vitro. Treatment of co-cultures with the myogenic factor IGF-I (p < 0.001) and the cytokines IL-13 (p < 0.05)
and IL-4 (p < 0.001) increased PNMA, while the myogenic inhibitors
Cytochalasin D (p < 0.001), Myostatin (p < 0.05), and TNFα
(p < 0.001) decreased PNMA. Furthermore, PNMA was increased upon
recovery from contraction-induced myotube damage (p = 0.052)
and LY29004-induced atrophy (p < 0.001). Moreover, siRNA mediated
knockdown of Myomaker in myoblasts (p < 0.001), but not in myotubes,
Conclusions: We developed a sensitive model system for quantitative assessment of in vitro
postnatal myonuclear accretion for the study of physiological and
pathological modulators of myogenesis, which allows distinction between
cell type specific roles of signals and responses in the regulation of
The overexpression of PGC-1α in the skeletal muscle affects myogenesis
Marc Beltrà, Fabrizio Pin, Riccardo Ballarò, Ambra Iannuzzi, Fabio Penna and Paola Costelli
Department of Clinical and Biological Sciences, University of Turin, Italy, Interuniversity Institute of Myology, Italy
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is
a master regulator of mitochondrial biogenesis. In skeletal muscle,
PGC-1α expression is induced by exercise. Along this line, transgenic
MCK-PGC-1α mice, which overexpress this transcription factor
specifically in the skeletal muscle, are characterized by enhanced
exercise performance in comparison with wild-type animals; this is
mainly due to increased myofiber mitochondrial content that results in
markedly improved energy metabolism. In addition to an increased
proportion of oxidative fibers vs glycolytic ones, we found a
high number of fibers with centrally located nuclei, which is indicative
of muscle regeneration. Moreover, myogenic stem cells are more abundant
in transgenic mice compared to wild-type animals. When cultured in
differentiating medium, cells isolated from PGC-1α mice form myotubes
larger than those generated by cells derived from wild-type animals.
Starting from this point, the aim of the study was to investigate if
stem cells from MCK-PGC-1α mice can improve myogenesis.
Muscles from male wild-type and MCK-PGC-1α mice were subjected to mild
digestion, and mononuclear cells were isolated by filtration. These
cells were then transplanted into the tibialis anterior muscle of female wild-type mice, either injured (BaCl2
i.m. injection 8 hours before cell transplantation) or not. The
animals were euthanized 12 days after BaCl2 injection.
Hematoxylin/eosin staining of muscles transplanted with WT-derived
cells shows improved regeneration. On the contrary, all the muscles
injected with MCK-PGC-1α-derived cells show an increase of centrally
located nuclei, altered myofiber cross-sectional area distribution and
marked SDH staining. The expression of molecular markers of regeneration
(Pax7, MyoG) and mitochondrial content (Tom20, COX-IV) is consistent
with the histological pattern.
Conclusions: The results
obtained in the present study suggest that cells isolated from
MCK-PGC-1α donor mice are able to fuse with recipient muscle myofibers
partially inducing a shift towards oxidative metabolism and affecting
Resistance exercise prevents cancer-induced muscle wasting in Ehrlich tumor-bearing mice
Rafael Deminice1, Mayra J. Testa1, Camila S. Padilha1, Fernando T. Frajacomo1, Poliana C. Marinello1,2, Paola S. Cella1, Felipe A. Moura1, Jose A. Duarte3, Rubens Cecchini2 and Flávia A. Guarnier2
1Department of Physical Education, State University of Londrina, Brazil; 2Department of Pathology, State University of Londrina, Brazil; 3CIAFEL, Faculty of Sport, University of Porto, Porto, Portugal
Background and aim:
Resistance exercise training (RET) is known to stimulate protein
synthesis and skeletal muscle hypertrophy in health subject. However,
RET effects on tumor-induced cachexia and muscle wasting are poorly
known. We aimed to evaluate cachexia and skeletal muscle plasticity
responses to RET after Ehrlich tumor cell inoculation.
Swiss mice were divided randomly into 4 groups: control (C),
tumor-bearing (T), exercised (E) and tumor-bearing exercised (TE).
Animals were inoculated with Ehrlich tumor cells (1 × 106
suspension in PBS) before RET that was performed for the following
4 wks. RET protocol consisted of climbing a ladder apparatus with
progressive load weights tied to the animal's tail in E and TE groups,
while the physical activity of C and T rats was confined to the space of
Results: Ehrlich tumor grew progressively (P < 0.05)
reaching 15% of animal's body weight after 4 wks. Tumor growth promoted
muscle wasting demonstrated by decreased gastrocnemius CSA (−28%, P < 0.05), body weight loss (−15%, P < 0.05) and decreased fat content. Increased (P < 0.05)
systemic leukocytes and pro-inflammatory interleukins were also
demonstrated in T animals compared to C. In contrast, RET was able to
mitigate the reduced body weight and muscle wasting by the attenuation
of systemic inflammatory markers. RET also prevented loss of muscle
strength and locomotor capacity associated with tumor development in
both experiments. Pro-inflammatory panel attenuation may down-regulates
protein degradation pathways in skeletal muscle and contributes to the
preventive anti-atrophy effects of RET. In addition, the Erlich tumor
microenvironment analysis demonstrated RET reduced the proliferation of
tumor cells and increases the necrotic tumor area without change tumor
Conclusions: RET prevented muscle wasting by
attenuating tumor-induced systemic pro-inflammatory. Our data also
suggest RET reduces tumor proliferation cells and tumor aggressiveness.
Supported by Capes-PVE #88881.068035/2014-01
Walker-256 tumour growth affects the 1H-NMR based metabolomic profile of skeletal muscle more severely in young-host compared to adult rats
Ophélie Ocean Orvoën1,2, Derly Floriano1, Bread Leandro Cruz1, Lais Rosa Viana1, Carla de Moraes Salgado1, Rogerio William dos Santos1, Luiz Alberto Ferreira Ramos1 and Maria Cristina Cintra Gomes-Marcondes1
of Nutrition and Cancer, Department of Structural and Functional
Biology, Biology Institute, University of Campinas (UNICAMP), Brazil; 2Université d'Angers, Angers, France
Cancer cachexia is an important clinical problem, which reduces the
life expectancy, mainly due to the marked body weight loss. The tumour
evolution leads to skeletal muscle mass wasting, mediated by the
proteolysis and/or reduced protein synthesis. We aimed to evaluate, by a
time-course study, the tumour growth correlation to the cachectic state
and also to muscle tissue metabolomic profile in Walker-256
Methods: Adult Wistar rats (A;
90 days) and young (Y; 21 days) were submitted to tumour implant
(2 × 106 viable cells). The animals euthanasia occurred at a different
time of tumour evolution (7th, 9th and 14th day for young; 7th, 14th and
21st day for adults) and compared to non-tumour-bearing rats. The
carcass, muscle and tumour weights were measured at each euthanasia day.
The metabolomic analysis of skeletal muscle samples were accessed by
using high-resolution 1H-NMR spectroscopy.
Results: We observed that young tumour-bearing rats had an increase in carcass-to-initial body weight ratio (58% higher; P = 0.0003), associated with a higher liver-to-carcass weight (67%; P < 0.0001)
when compared to A group. The cachexia index was bigger in young than
adult group (Y > A, 2.4×; P = 0.0001).
Even though, the muscle-to-carcass weight ratio was similar in Y and A
groups, as well as the tumour weight rate. The 1H-NMR analysis of muscle tissue showed differences mainly in the content of methylhistidine (Y > A, 10× higher; P = 0.0186), succinate (Y > A, 4.2×; P = 0.0255), dimethylglycine (Y > A, 12×, P < 0.0001),
and other metabolites. These differences showed some impacted metabolic
pathway such as nitrogen metabolism (P = 0.0128); alanine/aspartate/glutamate metabolism (P = 0.0339), and citrate cycle (TCA cycle; P = 0.0283) (analysed using http://www.metaboanalyst.ca).
The tumour evolution reduced the survival time in young rats (14 days)
comparing to the adult group (21 days), leading to severe damage effects
mainly related to muscle wasting, showing substantial implications in a
pathway contribution to the skeletal muscle wasting attenuation effect
of resistance exercise in Walker 256 tumor-bearing rats
Camila S. Padilha1, Fabrício A. Voltarelli2, Poliana C. Marinello1, Mayra T.J. Testa1, Paola S. Cella1, Philippe B. Guirro1, Kessi C. Iarosz1, Lilian E.C.M. Silva3, Alceu Afonso Jordão3, José A. Duarte4, Rubens Cecchini1, Flávia A. Guarnier1 and Rafael Deminice1
1State University of Londrina, Londrina, PR, Brazil; 2Federal University of Mato Grosso, Cuiabá, MT, Brazil; 3Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; 4CIAFEL, Faculty of Sport, University of Porto, Porto, Portugal
Resistance exercise (RE) is known to up-regulate Akt-mTOR signaling for
protein synthesis in skeletal muscle; however, RE effect on
tumor-induced muscle wasting is poorly known. We aimed to investigate
the Akt-mTOR pathway contribution to the skeletal muscle wasting
prevention promoted by resistance exercise in tumor-bearing rats.
Thirty-seven Wistar rats were divided into 4 groups: control (C,n = 9),
tumor-bearing (T,n = 9), exercised (E,n = 9), and tumor-bearing
exercised (TE,n = 10). Walker-256 tumor cells were implanted in the
right flank of T and TE groups. Forty-eight hours after tumor
implantation the animals started a four-week period of RE. RT protocol
consisted of climbing a ladder apparatus with weights tied to the
animal's tail in E and TE groups, while the physical activity of C and T
rats was confined to the space of the cage.
Results: The Walker-256 tumor grew progressively (P < 0.05)
reaching 4% of animal's body weight after 4 wks. Tumor growth caused a
reduced body weight gain (−9.85%) and muscle weight loss. Tumor growth
also decreased muscle strength (−11.09%), promoted skeletal muscle
atrophy (P75 = −24%) and increased skeletal muscle collagen deposit
(+87.5%). In addition, elevated systemic leukocytes (+150%), TNF-α
(+30.3%) and mRNA muscle levels of Atrogin-1 (+204%), but not changed
mTor skeletal muscle mRNA level were demonstrated in T rats compared to
C. In contrast, RE was able to attenuate loss of body weight (+6.35%)
and skeletal muscle weight (+12.5%). However, no changes in Akt-mTOR
were demonstrated in tumor-bearing rats after RE. Exercised
tumor-bearing animals presented attenuated muscle atrophy (P75 = −1.12%)
and collagen deposition, probably by attenuating elevated systemic
leukocytes (−31.5%) inflammatory interleukins and elevated mRNA
Atrogin-1 levels (−44.6%) caused by tumor growth.
RE attenuates cachexia development and muscle wasting, by
downregulating tumor-induced systemic inflammation and proteolysis
signaling, but not to enhances Akt-mTOR signaling.
Supported by Capes-PVE #88881.068035/2014-01
Catwalk XT system (natural gait evaluation) as a skeletal muscle functional measurement in preclinical study of cancer cachexia
Laís Rosa Viana1, William F. Vieira1, Natalia Tobar2, Gabrielly Machado1, Sílvio Roberto Consonni3, Bianca Castelucci3, Alexandre Leite Rodrigues de Oliveira1 and Maria Cristina Cintra Gomes-Marcondes1
of Nutrition and Cancer, Department of Structural and Functional
Biology, Biology Institute, University of Campinas (UNICAMP), Brazil; 2Nuclear Medicine Service of the Clinical Hospital of UNICAMP, Brazil; 3Department of Biochemystry and Tecidual Biology, Biology Institute, University of Campinas (UNICAMP), Brazil
Cancer cachexia is a wasting syndrome characterised by involuntary
weight loss caused mainly by skeletal muscle loss associated or not with
mobilisation of adipose tissue. Additionally, muscle function could be
severely jeopardised leading to a bad quality of life and poor treatment
outcomes. Few preclinical studies evaluate the loss of muscle function
in experimental models of cancer cachexia. Therefore, the aim of this
study was to evaluate whether CatWalk test (natural gait evaluation)
could be used to measure muscle function in cancer cachexia preclinical
Methods: As preclinical model of cancer cachexia,
Wistar rats were subcutaneously injected in the right flank with Walker
256 carcinoma (2.5 × 106 viable cells). Animals performed
CatWalk test previously (health) and posterior (pre-agonic state) of
tumour inoculation. For CatWalk analysis, we considered maximal contact
area (cm2), print area (cm2) and maximal intensity of hind limb and forelimb paws. We also evaluate muscle mass (g), muscle fiber cross sectional area (cm2) and fat mass using Dual-Energy X-Ray Absorptiometry (DEXA).
Results: Walker-256 tumour growth led to cachexia state manifested by significant weight loss (P = 0.001) due to loss of skeletal muscle mass (18.7%, P = 0.03), decreased muscle fiber cross section area (43.5%, P = 0.0001) and also by fat loss (35.8%, P < 0.0001).
CatWalk measurements at pre-agonic state showed a significant reduction
in the maximal contact area and the print area of hind limb paws
(46.9%, P = 0.0196 and 46.1%, P = 0.0112) and the maximal paw footprint intensity decreased in both fore and hind limb (5.83%, P = 0.0024 and 6.8%, P = 0.0143).
The high sensitivity of the motor dynamic function analysis by the
CatWalk method was able to characterise the loss of muscle function in
this experimental model of cachexia and also showed that these
functional parameters were correlated with the other morphometric
Mitochondrial dysfunction promotes cancer-induced cardiac and respiratory muscle weakness
Michael P. Wiggs1, Brandon M. Roberts2, Oh-Sung Kwon3, Jeung-Ki Yoo3, Demetra D. Christou3, Andrew R. Judge2, David D. Fuller2, Hazel H. Szeto4 and Ashley J. Smuder5
1Department of Health and Kinesiology, University of Texas at Tyler, Tyler, TX, USA; 2Department of Physical Therapy, University of Florida, Gainesville, FL, USA; 3Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; 4Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA; 5Department of Exercise Science, University of South Carolina, Columbia, SC, USA
Cancer cachexia is a syndrome characterized by profound cardiac and
diaphragm muscle wasting, which increase the risk of morbidity in
cachectic patients due to failure of the cardiorespiratory system. In
this regard, muscle relies greatly on mitochondria to meet energy
requirements for contraction and mitochondrial dysfunction can result in
muscle weakness and fatigue. In addition, mitochondria are a major
source of reactive oxygen species (ROS) production, which can stimulate
increased rates of muscle protein degradation. Therefore, it has been
suggested that mitochondrial dysfunction may be an underlying factor
that contributes to the pathology of cancer cachexia.
To determine if inhibition of mitochondrial dysfunction is sufficient
to prevent cancer-induced muscle dysfunction, colon 26 (C-26)
tumor-bearing mice were administered either saline or the mitochondrial
peptide SS-31 daily (3 mg/kg/day). Specifically, SS-31 is a
multifunctional peptide that has been demonstrated to preserve
mitochondrial function during atrophic conditions by inhibiting
cardiolipin peroxidation and reducing ROS production.
C-26 mice treated with saline demonstrated greater rates of ROS
emission and mitochondrial uncoupling compared to C-26 mice receiving
SS-31 in both the heart and diaphragm muscle. In addition, SS-31
administration to C-26 mice attenuated both cardiac and diaphragm muscle
dysfunction. Indeed, cancer cachexia-induced alterations to the
myocardial performance index and the percentage fractional shortening
were significantly rescued in C-26 mice treated with SS-31. In the
diaphragm, muscle fiber cross-sectional area of C-26 mice treated with
saline was significantly reduced, and force production was impaired
compared to C-26, SS-31 treated animals. Finally, ventilatory deficits
were also attenuated in tumor-bearing animals treated with SS-31,
compared to those treated with saline.
data demonstrate that cancer promotes severe cardiac and respiratory
myopathy and that prevention of mitochondrial dysfunction is sufficient
to preclude cancer cachexia-induced cardiorespiratory dysfunction.
tyrosine kinase inhibitors imatinib, sorafenib and sunitinib perturb
energy metabolism and cause cytotoxicity to C2C12 murine skeletal muscle
Vijaya L. Damaraju1, Michelle Kuzma2, Carol E. Cass1 and Michael B. Sawyer1,2
1Department of Oncology, University of Alberta; 2Cross Cancer Institute, Edmonton, AB, Canada
Tyrosine kinase inhibitors (TKIs) have improved cancer treatment and
prognosis but have also resulted in side effects that include fatigue,
diarrhea, hypothyroidism, and other toxicities. Because TKI effects on
mitochondrial function are thought to play a role in cardiac myocyte
dysfunction, we investigated TKI effects on skeletal muscle as a
possible explanation of TKI fatigue. Mitochondrial dysfunction can
result from inhibition of oxidative phosphorylation complexes and
superoxide generation. It is also likely that inhibition of key
transporters involved in uptake of glucose and/or nucleosides could also
result in alteration of energy metabolism or mitochondrial mass. In
this work, we investigated these processes in cultured C2C12 murine
skeletal muscle cells.
Methods: We studied imatinib,
sorafenib and sunitinib effects in C2C12 cells grown under conditions
that result in formation of myotubes by measuring mitochondrial complex
activity, ATP production, caspase activation, mitochondrial membrane
potential, reactive oxygen species (ROS) generation and nucleoside and
Results: Imatinib was cytotoxic and
inhibited complex V activity. Imatinib had negligible effects on ATP
levels, ROS generation or membrane potentials, but stimulated glucose
uptake. Sunitinib caused cytotoxicity, ATP level depletion, apoptosis
activation, increase in ROS, and decrease in mitochondrial membrane
potential and nucleoside and glucose uptake. Sorafenib was cytotoxic
with rapid activation of caspase 3/7 activity. Sorafenib inhibited
complex III and V quite potently, but there was no increase in
generation of mitochondrial superoxide, although depolarization of
mitochondrial membranes occurred very rapidly with complete loss at
5–10 μM sorafenib.
Conclusions: Imatinib, sunitinib and
sorafenib through different mechanisms caused changes in mitochondrial
complex activities, glucose and nucleoside uptake leading to decreased
energy production and decreased mitochondrial function in a skeletal
muscle cell model, suggesting that these effects play a role in fatigue,
one of the most common TKI side effects.
Pericyte in the adult muscle satellite cell niche: a key player maintaining the steady state and helping recovery
Koumaiha Zeynab1, Baptiste Périou2, Muriel Rigolet2, Frederic Relaix1,3, Romain Gherardi2,3 and Peggy Lafuste1
1INSERM IMRB U955, Team 10 group 1, University of Paris-Est Creteil, France; 2INSERM IMRB U955, Team 10 group 2, University of Paris-Est Creteil, France; 3Henri Mondor Hospital, Department of Pathology, University of Paris-Est Creteil, France
Muscle growth and post-injury regeneration are supported by muscle
satellite cells (mSCs) that reside beneath the myofiber basement
membrane in close proximity to capillaries. We previously showed that
pericytes play a key role in the microvascular niche of mSCs during
post-natal stages of muscle growth, by promoting post-natal myogenesis
through IGF-1 and inducing mSC quiescence ending the accretion phase
through Angiopoietin-1. Since 90% of capillaries have pericyte coverage
at the end of muscle growth, we investigated the role of pericytes in
the adult mSC niche.
Material et methods: We used TNAP-CreERT2 mice crossed with R26RDTRstoploxP/stoploxP, Angiopoietin-1loxP/loxP, and R26RmTloxPmG/loxPmG
animals to generate respectively conditional models for diphteria
toxin-induced muscle depletion of microvascular cells, ablation of
microvascular Angiopoietin-1 and fluorescent tracing of microvascular
Results: Conditional muscle pericyte depletion could
not be used due to extensive, presumably ischaemic, muscle necrosis. In
contrast, selective Cre recombinase ablation of Angiopoietin-1 gene in
TNAP+ pericytes induced release of adult mSCs from
quiescence. Following chemical injury, the ablation caused delayed
muscle regeneration with persistently cycling Pax7+ mSCs.
Selective Type 2 fiber hypotrophy was observed consistently with
prominent association of TNAP-expressing microvessels with type 2 fibers
observed in TNAP-GFP reporter mice.
conclude that pericytes associated with endothelial cells exert
paracrine effects on adjacent myogenic cells that are essential to
maintain adult muscle homeostasis and during muscle repair.
Circulating hormones and neuropeptides profile in cachectic colorectal cancer patients
Estefanía Simoes Fernández1,2, Joanna Darck Carola Correia Lima1, Raquel Galvão Figueredo1, Emidio Marques de Matos-Neto1, Gabriela Salim de Castro1, Fang Chia Bin5, José Pinhata Otoch1,3,4, Paulo Sergio Martins de Alcantara3, Alessandro Laviano6 and Marília Seelaender1,4
1Cancer Metabolism Research Group, University of São Paulo, Brazil; 2Department of pathological anatomy, University Hospital, University of São Paulo, Brazil; 3Department of Clinical Surgery, University Hospital, University of São Paulo, Brazil; 4Faculdade de Medicina, University of São Paulo, Brazil; 5Santa Casa de Misericórdia de São Paulo, Brazil; 6Department of Clinical Medicine, Sapienza University of Rome, Italy
Cancer Cachexia is a devastating and multifactorial syndrome involving
changes in several metabolic pathways, in many tissues and organs. It is
defined as a muscle-wasting syndrome, with or without adipose tissue
atrophy. Anorexia, fatigue, asthenia, anaemia, insulin resistance and
systemic inflammation are symptoms commonly related to the syndrome,
leading to a poor prognosis and reduced survival. Furthermore,
circulating hormones and neuropeptides, directly related to peripheral
signals from the Central Nervous System, could play a key role
contributing in the regulation of energy homeostasis and influencing
Aim: To evaluate circulating hormones and
neuropeptides and to elucidate possible modified pathways related to
appetite regulation and weight control in cancer cachexia patients.
Methods: Patients with colorectal cancer were divided into Weight-Stable Cancer (WSC, n = 42) and Cachectic Cancer (CC, n = 44)
groups. Blood sampling was performed after signature of the informed
consent form. Hormones and neuropeptides were quantified with Luminex®
Results: Serum samples from cachectic patients presented significant lower levels of circulating amylin and insulin, compared to WSC (p < 0.0004 and p < 0.0001, respectively). Moreover, Leptin (p < 0.0002) and gastric inhibitory polypeptide (GIP) (p < 0.0009)
were both significantly decreased in CC patients. Finally, no
differences were observed between WSC and CC for the other hormones
(Glucagon, C-Peptide, pancreatic polypeptide (PP), Peptide YY (PYY);
glucagon-like peptide-1 (GLP-1); Ghrelin). Finally, the neuropeptides
Orexin A (p < 0.0195) and Oxytocin (p < 0.004)
were decreased in CC patients, maybe contributing to the behavioural
changes generally related to the syndrome.
The results show robust modulation by cachexia of patient circulating
hormone and neuropeptides, factors directly related to appetite
regulation, energy homeostase and food intake. For that reason, the
results point out to a possible beneficial effect of hormone therapy.
Furthermore, neuropeptide changes might be related with behavioural
changes, a major problem in cachexia that remains poorly investigated.
TAPT: its role in tumoral microenvironment
Nelson Inácio Pinto Neto1, Diego Alexandre Cavalaro2, Valter Tadeu Boldarine1, Ana Claudia Losinskas Hachul1, Joanna Darck Carola Correia Lima2, Marilia Seelaender2, Claudia Oller do Nascimento1 and Lila Missae Oyama1
1Universidade Federal de São Paulo, São Paulo, Brazil; 2Universidade de São Paulo, São Paulo, Brazil
The adipose tissue is an endocrine organ that secretes a wide range of
molecules, including the adipokines. Adipocytes also produce angiogenic
and growth factors that contribute to progression of solid tumors such
VEGF and TGF-β, respectively. These adipokines and the peritumoral
adipose tissue may have an important role in cancer biology and
carcinogenesis, considering the possible crosstalk between the
peritumoral adipose tissue and tumour.
Methods: 16 patients enrolled in this study was divided as follows: patients with cancer without cachexia-WSC (n = 7) and patient with cancer cachexia-CC (n = 9).
The study was approved by the Ethics Research Committee (972.914).
Samples of peritumoral adipose tissue were removed for determination of
TNF-α, IL-1β, STAT-1, STAT-3, RANTES, IL-1Ra, IOp-10, IL-15, MCP-1,
IFN-α, GCSF, FADD, and TGF-β concentration. Also, correlation between
these proteins and cytokines was analyzed.
and FADD, factors involved with apoptosis, were significantly higher in
CC as compared to WSC. Also, IL-1β and STAT-1 were significantly lower
in CC as compared to WSC. In the TAPT of CC, a significant positive
correlation of RANTES with IL-1Ra and IP-10 and a negative correlation
(RANTES/IFN-α) were found. Analysis of correlation of GCSF with the
protein content of IL-1Ra, IP-10, IL-15 and MCP-1 showed a significant
negative relationship and a positive correlation with IFN-α. In TAPT of
WSC no significant correlations were detected between RANTES, GCSF,
IL-3, FADD and STAT-1 and cytokines/chemokines analyzed.
These results indicate that inflammatory and tumorigenic pathways are
altered in peritumoral adipose tissue during cancer cachexia.
Furthermore, we demonstrate that in peritumoral adipose tissue of
cachectic patients, inflammatory cytokines are correlated with growth
factors, pointing to a modulation of the proliferative environment in
close proximity to the tumor by inflammatory cytokines.
Sexual dimorphism in human cancer cachexia: a preliminary study into miRNA/mRNA expression in human skeletal muscle
Ashok Narasimhan1, Russell Greiner1, Oliver F. Bathe2, Vickie Baracos1 and Sambasivarao Damaraju1
1University of Alberta, Edmonton, Canada; 2University of Calgary, Calgary, AB, Canada
Cancer cachexia (CC) is a multifactorial syndrome characterized by
severe depletion of skeletal muscle, with or without fat loss. Gene
expression studies have identified several genes associated with CC;
however, sex-specific expression differences have never been studied.
To profile microRNAs (miRNAs) and differential gene expression at the
isoform level (DEI) in human skeletal muscle biopsies to understand the
sex-specific expression differences in CC and mRNA isoform regulation by
Methods: 42 cancer patients were classified into
cachectic cases based on International diagnostic consensus framework
for CC, and non-cachectic controls—cancer patients who were weight
stable for six months compared to pre-illness weight. While 9 men and 13
women were cachectic cases, 9 men and 11 women were non-cachectic
controls. Next generation sequencing and Affymetrix Human Transcriptome
array 2.0 were used to identify miRNAs and DEI, respectively.
Representative miRNAs and DEI were validated using qRT-PCR.
Differentially expressed (DE) miRNAs and DEI were identified at 1.4 FC
at p < 0.05 using Partek genomics suite 6.6.
10 DE miRNAs (9 in autosomes and 1 in X chromosome) were identified in
men, and 3 DE miRNAs (autosomal) were identified in women, and none were
common between the two sexes. 1324 and 372 DEI were identified in men
and women respectively and showed limited overlap (3%). qRT-PCR results
showed cross-platform concordance for both miRNA and DEI. Validation of
DE miRNAs in an independent dataset confirmed these findings. While
skeletal muscle atrophy associated pathways were prominent in men,
adipogenesis pathways were seen in women. TGFB1 was identified as a
common upstream regulator in both sexes. However, their downstream
targets were different.
Conclusions: The preliminary study
identifies sex-specific expression in CC at the miRNA, DEI and at the
pathway levels. Functional characterization of these molecules is
warranted to delineate their mechanisms in CC pathophysiology.
Displaced myonuclei in cancer cachexia suggest altered innervation
Dario Coletti1,2, Hassani Medhi1,2, Nissrine Daou1, Matos Emidio3, Raquel Galvao Figueredo3, Gabriela Salim De Castro3, Viviana Moresi2, Adamo Sergio2, Li Zhenlin1 and Marilia Seelaender3
of Biological Adaptation and Ageing B2A (CNRS UMR 8256 - INSERM ERL
U1164 - UPMC P6), Pierre et Marie Curie University Paris 6, France; 2DAHFMO Unit of Histology and Medical Embryology, and Interuniversity Institute of Myology, Sapienza University of Rome, Italy; 3Institute of Biomedical Sciences, University of Sao Paulo, Brazil
Central nuclei are considered a hallmark of skeletal muscle fiber
regeneration and a sign of myopathy. We and others have previously
observed central myonuclei in both pre-cachectic patients and animal
models of cancer cachexia, in striking contrast with the reduced
regenerative potential characterizing cachectic muscles.
To elucidate the mechanisms underlying these divergent observations we
further characterised the nature of central nuclei, and the muscle fiber
involved, in both pre- and cachectic cancer patients, as well as in
C26-tumor-bearing mice. Muscle with different physiological properties,
the Rectus abdominis and the Tibialis anterior, was analysed in search of denervation and regeneration markers.
We observed rare though measurable, non-peripheral myonuclei. The
latter consisted of two distinct population: bona fide central nuclei
and nuclei that are neither central nor subsarcolemmal, which we named
«displaced» myonuclei. Displaced and central nuclei were detected in all
types of muscle fibers. However, displaced myonuclei were the only ones
to vary between control and cachectic muscles, suggesting a link with
the pathological condition. Non-peripheral myonuclei were observed in
the absence of muscle regeneration molecular markers, such as embryonic
or fetal myosin expression. The analysis of longitudinal sections
revealed that displaced myonuclei are clustered as it occurs upon
denervation, and that the number of nuclear clusters increases in
cachexia, coincident with N-CAM upregulation, another denervation
marker. Additional denervation markers were upregulated in both human
and murine cachectic muscles.
Conclusions: We observed a
novel phenomenon in cancer patients and animal models of cachexia: the
presence of displaced nuclei consistent with motor neuron loss or NMJ
perturbation. This phenomenon could underlay a previously neglected
phenomenon of denervation rather that myofiber damage and regeneration
in cachexia. Like in aging, denervation-dependent myofiber atrophy could
contribute to the atrophic process leading to muscle wasting.
Cachexia mechanisms in cancer through the lens of transcriptomics
Kolitz, Kevin D. Fowler, Jason M. Funt, Jenny Zhang, Matthew Ung, Renan
Escalante-Chong, Andrew C. Lysaght, Gregory Koytiger, Yoonjeong Cha and
Immuneering Corporation, Cambridge, MA, USA
Cachexia is a major clinical complication that affects up to 80% of
patients with advanced cancer, and by some estimates is responsible for
20% of cancer deaths .
Despite its role in cancer mortality, no approved therapies are yet
available, and the mechanisms underlying cachexia remain to be fully
Methods: Gene expression profiling provides a
quantitative means to systematically assess biological differences
between tissue from patients who develop cachexia and from those who do
not. Here, we report cachexia-related findings from computational
analysis of publicly accessible gene expression datasets from various
biological contexts, including a dataset with adipose tissue from cancer
patients with and without cachectic weight loss (E-GEOD-51931) .
Genes and pathways identified by these analyses include currently known
cachexia mechanisms, and also emerging mechanisms that have not
historically been emphasized in cachexia research. Some of these
emerging mechanisms may help to more fully explain the consequences of
the well-known association between inflammation and cachexia and support
the previously described importance of Pax7 in cachexia .
Transcriptomics is a powerful approach for dissecting the molecular
underpinnings of cancer cachexia and prioritizing areas for drug
development. Our findings suggest new avenues for experimental follow-up
and highlight new possibilities for the treatment of cachexia in cancer
- 1Nat Rev Cancer (2014) 14:754–762 et al,
- 2Br J Cancer (2010) 10:1541–1548 et al,
- 3J Clin Invest (2013) 123:4821–4835 et al,
Blocking adipose tissue lipolysis does not prevent muscle wasting in an experimental cancer cachexia model
Sílvia Busquets1,2, Marta Castillejo1, Cristina Moreno1, Ecem Tuna1, Marina Bantulà1, Tessa van Daalen1, Francisco J. López-Soriano1,2 and Josep M. Argilés1,2
Research Group, Departament de Bioquímica i Biomedicina Molecular,
Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; 2Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
Introduction and Purpose: A previous study
through genetic ablation of adipose triglyceride lipase (ATGL)
concluded that blocking the lipolytic machinery prevented the loss of
muscle wasting in mouse models of cancer cachexia (Lewis lung carcinoma
and B16 melanoma). Bearing this in mind, the objective of the present
study was to block all the lipolytic enzimes present in adipose tissue
(using chemical inhibitor) to see if muscle wasting could be avoided
using this pharmacological strategy.
Methods: We used Acipimox to block lipolysis, Atglistatin to inhibit ATGL, and Compound 12 to inhibit hormone sensitive lipase (HSL).
The results obtained clearly show that, despite the decrease in
circulating free fatty acids caused by the inhibition of lipolytic
enzymes, no changes in the muscle loss associated with cancer cachexia
Conclusions: It is therefore concluded that preventing adipose tissue wasting does not influence muscle atrophy associated with cancer.
- 1Adipose triglyceride lipase contributes to cancer-associated cachexia. Science. 333, 233–8 (2011). et al.
Long non-coding RNA profiling in human skeletal muscle and their role in Cancer Cachexia
Bhumi Bhatt1, Ashok Narasimhan1, Oliver Bathe2, Vickie E. Baracos1 and Sambasivarao Damaraju1
1University of Alberta, Edmonton; 2University of Calgary, Calgary, AB, Canada
Introduction: lncRNAs (long non-coding RNAs, >200 bp)
regulate gene expression by transcriptional, post-transcriptional and
epigenetic mechanisms. lncRNAs originating in gene regions may regulate
the coding genes. lncRNAs act as decoys and scaffolds for miRNAs and
transcription factors, respectively, to regulate gene expression.
lncRNAs are known to be dysregulated in a tissue- and disease-specific
context. Expression and regulation of lncRNAs in human skeletal muscle
under conditions of cancer cachexia remains to be elucidated.
i) To profile lncRNAs from human skeletal muscle biopsies from
cachectic and non-cachectic cancer patients; ii) to identify
differentially expressed (DE) lncRNAs; iii) to identify muscle-specific
transcription factor gene expression to explain transcriptional
regulation of lncRNAs.
Methods: Study subjects (n = 40)
were classified as cachectic cases and non-cachectic controls based on
international consensus diagnostic criteria (high %weight loss with
sarcopenia or low BMI). Total RNA was extracted from muscle biopsies and
mRNA and lncRNAs were profiled using Human Transcriptome Array-2.0.
Data were analysed using Partek Genomics Suite. DE analysis was done
using one-way ANOVA, and lncRNAs were annotated using Gencode database.
Annolnc database was used for functional insights into lncRNAs.
Results: 62 lncRNAs were identified as DE (fold change range −1.2 to 1.58 and p < 0.05),
of which 13 were down-regulated and 49 were up-regulated in cachectic
cases. Reciprocal expression of the DE representative lncRNA-nearest
mRNA pairs noted were RP11-420G6.4-SERPINB9P1; CTA-292E10.6-001-XBP1;
RP11-587D21.4-001-BDNF; and RP11-196G18.22-HIST2H2BC, suggestive of
transcriptional regulatory mechanisms.
We predicted transcription
factor binding sites in the lncRNAs and a subset of these also showed DE
in muscle: e.g. ZNF143, CHD1/2, SMC3, HDAC2, NFYB, MEF2C; these need to
be validated in functional assays.
identified DE lncRNAs associated with cancer cachexia. Our current
efforts are also to identify how lncRNAs act as decoys to sequester
miRNAs and contribute to the pathophysiology of cachexia.
Blood cells in cancer cachexia: it is easy to spot the difference
Ana Flávia Pessoa1,2,3,4, Raquel G. Figuerêdo1, Paula C. Leme1, Katrin Radloff1, Luis Henrique Andrade1, Fernanda Formiga5, Ana Paula Lepique1, Alessandro Laviano6, Paolo S. Alcantara5 and Marilia Seelaender1
1Institute of Biomedical Sciences University of São Paulo, São Paulo, SP, Brazil; 2University of São Paulo Medical School (FMUSP), São Paulo, SP, Brazil; 3Federal University of Piaui, Teresina, PI, Brazil; 4Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, SP, Brazil; 5University Hospital of the University of São Paulo, São Paulo, SP, Brazil; 6Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
Cachexia is a multifactorial syndrome whose hallmark is weight loss and
systemic inflammation. Despite the relevance of cachexia as a health
system burden, finding feasible diagnostic methods remains a challenge.
Aim: Characterization of blood cellularity and biochemical parameters in cancer cachexia.
Non-cancer patients (CONTROL), weight stable (WSC) and cachectic
gastrointestinal cancer (CC) patients participated in the study approved
by the University of São Paulo Biomedical Sciences Institute (CEP
788/07) and University Hospital Ethics Committee (CEP 752/07, SISNEP
CAAE: 0031.0.198.019.07). Informed consent was obtained from all
participants. Patient group division was based on the criteria proposed
by Evans et al., 2008. Blood samples were collected to evaluate
the protein expression of CCL-2 and CCL-3 using Multiplex Magpix®
technology. The numbert of lymphocytes, neutrophil, platelets and MDSCs
(Myeloid Derived Suppressor Cells) was assessed by flow cytometry.
The number of lymphocytes was decreased in CC, whereas that of
platelets, neutrophils, the neutrophil-lymphocyte ratio (NLR) and the
PLR (Platelets Lymphocytes Ratio) were increased in CC when compared to
CONTROL and WSC. In CC, the concentration of circulating chemokine CCL-2
was higher than that of WSC patients.
results demonstrate increased NLR and PLR ratios as systemic
inflammatory parameters in cancer cachexia. The easy evaluation of NLR,
PLR makes them promising diagnostic tools. The increased platelets
levels and the higher number of circulating MDSCs also seem to be
specific for the immune phenotype of CC patients.
The TGF-b family cytokine MIC-1/GDF15 has differential effects on lean mass in normal and obese mice
Samuel N. Breit1,2, Hong Ping Zhang1, Rakesh Manandhar1, Yasmin Husaini1,2, Michelle Lee-Ng1, Helene Lebhar2, Christopher P. Marquis2, Amanda Sainsbury3, David A. Brown1,2 and Vicky W.W. Tsai1,2
1St Vincent's Centre for Applied Medical Research, St Vincent's Hospital Sydney, NSW, Australia; 2The University of New South Wales, Sydney, NSW, Australia; 3The
University of Sydney, The Boden Institute of Obesity, Nutrition,
Exercise & Eating Disorders, Charles Perkins Centre, NSW, Australia
MIC-1/GDF15 is a physiological appetite regulator, which when markedly
overproduced in some disease states, such as advanced cancer, causes an
anorexia/cachexia syndrome mediated, at least in large part, by its
actions on appetite control centres in the brain. Antibodies to
MIC-1/GDF15 have been proposed as therapeutics for patients with some
anorexia cachexia syndromes and recombinant MIC-1/GDF15 protein as an
Methods: In order to better understand
how prolonged elevation of MIC-1/GDF15 might impact animals with
differing adiposity, we have infused normal chow fed mice and those with
diet induced obesity, with either vehicle or highly purified, yeast
derived, recombinant murine MIC-1/GDF15 (0.5 ug/gBW/day), delivered over
28 days, by an osmotic minipump.
serum MIC-1/GDF15 levels in these mice reached an average of about
between 10 and 12 ng/ml, levels that are commonly reached in patients
with advanced cancer. Over this time, both groups of mice experienced a
substantial reduction in body weight in association with a reduction in
energy intake (13–15%) that was similar in both groups. The reduction in
body weight was significantly greater in obese than in lean mice
(15.54 ± 1.5% vs 10.28 ± 1.12%). Moreover, weight loss in obese mice was
due exclusively to loss of fat mass, with no significant loss of lean
mass. In contrast, the normal mice showed significant reductions in both
lean and fat mass. MIC-1/GDF15 effectively corrected the
pro-inflammatory metabolic abnormalities that frequently accompany
obesity in both this mouse model and as is well known to occur in
Conclusions: The differential effects of
MIC-1/GDF15 on lean and obese mice may explain the relative protection
from the anorexia/cachexia syndrome afforded by having an increased BMI
Identification of tumor-borne mediators secreted via exosomes triggering alterations in fat and muscle tissues in cancer cachexia
Victor Laurent, Sören Fisker-Schmidt, Maria Rohm, Stephan Herzig and Mauricio Berriel Diaz
for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg,
Germany, and Joint Heidelberg-IDC Translational Diabetes Program,
Heidelberg University Hospital, Heidelberg, Germany
Cancer cachexia is strongly associated with different types of tumors
and negatively affects quality of life, efficacy of tumor treatment and
survival of cancer patients. Despite its clinical importance, the
identity of tumor-borne signals inducing wasting and their impact on
specific peripheral organ systems remain mostly unknown. Exosomes have
been shown to be key mediators of the crosstalk between tumor cells and
their microenvironment. Nevertheless, only very few studies have focused
on the role of tumor cells derived-exosomes on cancer cachexia.
In an unbiased differential secretome analysis of colon cancer
cells-derived exosomes combined with high-throughput adipocytes and
myotubes phenotyping, we defined a list of exosomal proteins which
potentially had cachexia-inducing properties.
using overexpression strategy in HEK293 cells, different mouse models
for both colorectal and pancreatic cancer and human serum samples, we
confirmed that tumor-derived exosomal proteins contributed to skeletal
muscle atrophy and adipose tissue wasting in vitro and in vivo.
Our study suggests that tumor cell-derived exosomes are important
mediators of different components of cancer cachexia, which could
potentially provide novel opportunities for diagnostic and therapeutic
measures to alleviate cachexia, thereby contributing to improved disease
Comparison of whole genome gene expression in (cancer) cachectic muscles of animal models and human patients
Rogier L.C. Plas1, Guido J.E.J. Hooiveld1, Renger F. Witkamp1 and Klaske van Norren1,2
1Division of Human Nutrition, Wageningen University and Research, Wageningen, The Netherlands; 2Nutricia Research, Utrecht, The Netherlands
Different animal models are used to study mechanisms and treatment
options of (cancer) cachexia. Next to this, experimental conditions may
vary for the same model. In some studies, whole genome gene expression
of muscle tissue is measured using micro array analysis. Upon
publication of these gene expression studies, raw data are often made
available via the NCBI Gene Expression Omnibus database. By comparing
these datasets, differences and similarities between models and
experimental conditions can be examined. Moreover, knowledge can be
gathered on underlying processes causing muscle wasting and possible
differences between animal models for cancer cachexia and human cancer
cachexia. We are currently comparing different datasets containing
muscle gene expression of animal models and human tissue (on-line
available) and one of our own new and unpublished datasets containing
microarray data of heart muscle and m. extensor digitorum longus and m. soleus of mice from a C26 model.
differences and commonalities in whole genome gene expression between
different muscle tissues in (cancer) cachexia mouse models.
differences and commonalities in whole genome gene expression between
(cancer) cachexia mouse models and muscle from cachectic colon cancer
Methods: All datasets (our own and those
online available) are quality checked, normalised and annotated using
the latest CDF available. Comparisons are made both on gene and on
Hypotheses: We hypothesise that main
differences exist between different models and that smaller differences
occur due to different muscle types analysed for a certain model.
Moreover, we hypothesise that these smaller differences are due to
different effects of cachexia on specific muscle fibre types. We also
hypothesize that some models mimic the human situation better than
Currently, analysis is ongoing. At the conference the data
on comparison of different animal models and human samples will be
available and presented.
effect of n-3 fatty acid-derived amines and gut-derived bacterial
compounds on excretion of tumour-derived inflammatory mediators
Klaske van Norren, Mieke Poland, Rogier Plas, Frouwkje Politiek, Milena Banic, Jocelijn Meijerink and Renger Witkamp
Nutrition & Pharmacology group, Wageningen University, Wageningen, The Netherlands
To investigate the role N-3-derived-acyl-amines on the release of
cachexia-inducing inflammatory-mediators by colon adenocarcinoma (C26)
Background: N-3 fatty acids have been reported to be
able to reduce the cachectic inflammatory response. The effectivity of
the anti-cachectic response on N-3 fatty acids, however, seems to vary
between patients and study populations. We hypothesize that the
diversity of the response to N-3 fatty acids might be due to the ability
of an individual to form specific endogenous metabolites (acyl-amines)
from these fatty acids.
Methods: C26 cells were incubated
for 24 h in the presence and absence of Docosahexaenoic acid (DHA),
docosahexaenoyl ethanolamide (DHEA) and docosahexaenoyl serotonin
(DHA-5-HT). To stimulate IL-6 release, cells were incubated with
lipopolysaccharide (LPS) and Pam3CysSerLys4 (Pam3CSK4).
Interleukin (IL)-6 and PGE2 release were measured using enzyme-linked
immunosorbent assays (ELISAs). Data represent the average of n = 3
independent experiments. Statistical analysis was performed using
one-way analysis of variance (ANOVA) and Dunnett's post hoc testing. A
p-value <0.05 was considered statistically significant.
Results: PGE2 excretion was inhibited by both DHEA and DH-5-HT, but not significantly by DHA. Incubation with 0.5 μg/ml LPS or Pam3CSK4
was needed to induce IL-6 excretion, which was not measurable in
unstimulated cells. 1 μM DHA-5-HT reduced the LPS- and Pam3CSK4-induced IL-6 release. Both DHA and DHEA had no effect on IL-6 release.
Unstimulated cells produced PGE2, but did not produce IL-6. This is
surprisingly because the C26 mouse model shows an IL-6-dependent
development of cachexia. We therefore hypothesize that passage of
bacterial compounds through the gut-barrier might trigger the excretion
of tumour-derived cachexia-inducing inflammatory mediators in this
model. Acyl-amine-derivatives of DHA were far more effective than DHA in
inhibiting the excretion of PGE2 and IL6. These results suggest that
the metabolic fate of food derived n-3 fatty acids might influence the
anti-cachectic properties of these fatty acids.
Tumour growth changed the serum metabolomic profile in ageing rats
Rafaela Rossi Rosolen, Lais Rosa Viana, Rogerio Willian Santos and Maria Cristina Cintra Gomes-Marcondes
of Nutrition and Cancer, Department of Structural and Functional
Biology, Biology Institute, University of Campinas (UNICAMP), Brazil
The neoplasia development promotes host's biochemical and metabolic
alterations that culminate in the involuntary weight loss mainly due to
spoliation of muscle protein. This process results in a severe syndrome
called cachexia, which reduces the quality of life and survival in
cancer patients. This study aimed to analyse the tumour evolution and
the alterations in metabolic pathways during the ageing process in
Walker-256 tumour-bearing rats.
Methods: Ageing Wistar rats
(400 days old) were distributed into six different groups: Ageing
control (CS); Walker-256 tumour-bearing rats euthanized in various days
of tumour evolution: group euthanized at 11th (W11); 14th (W14); 17th
(W17); 21st (W21) and 25th (W25) days. The tumour implant occurred by a
single inoculation of 2 × 106 viable neoplastic cells in the
right flank subcutaneous. These all groups were also compared with adult
control (CA; 90 days old). The animals' serum samples were collected,
filtered and processed to access the metabolomic profile analysis by
using high-resolution 1H-NMR spectroscopy to evaluate the metabolites/pathways that may be involved in the process of cancer cachexia.
The tumour evolution showed an exponential growth curve, associated
with marked loss of body weight. The effects of tumour growth led to an
crescent increase in concentration of allantoin (W25 > S, 1.8-fold; P = 0.0047), 2-hydroxybutyrate (W25 > S, 10.7-fold; P = 0.0108), tryptophan (W25 > S, 2.6-fold; P = 0.0011) and n-methylhistidine (W25 > S, 12.2-fold; P = 0.0027), associated with marked reduction of serum glutamine (W25 80% lower; P = 0.0317) and glutamate (W25 34% lower; P = 0.0112). These changes led to impacted metabolic pathways such as glutamine/glutamate metabolism (P = 0.00001), nitrogen metabolism (P = 0.0128) and alanine/aspartate/glutamate metabolism (P = 0.0339).
These results show that tumour evolution requires energy and structural
substrates such as glucose and glutamine and promotes intense host
spoliation, such as protein degradation leading to an intense muscle
mass waste (higher methylhistidine), inducing a severe weight loss,
which culminates in host cachectic state.
mitochondrial metabolic reprogramming agent trimetazidine as an
‘exercise mimetic’ and myogenesis promotor in cachectic C26-bearing mice
Elisabetta Ferraro1, Francesca Molinari1, Fabrizio Pin2,3, Stefania Gorini1, Sergio Chiandotto4, Fabio Penna2,3, Emanuele Rizzuto5, Antonio Musaro6,7, Paola Costelli2,3 and Giuseppe Rosano1,8
1Laboratory of Pathophysiology of Cachexia and Metabolism of Skeletal Muscle, IRCCS San Raffaele Pisana, 00166, Rome, Italy; 2Department of Clinical and Biological Sciences, University of Turin, Italy; 3Interuniversity Institute of Myology-IIM; 4DMCM
Department of Molecular and Clinical Medicine, c/o Department of
Surgery "Pietro Valdoni", Sapienza University of Rome, Italy; 5Department of Mechanical and Aerospace Engineering, Sapienza University of Rome, 00184, Rome, Italy; 6Institute
Pasteur Cenci-Bolognetti, DAHFMO-Unit of Histology and Medical
Embryology, IIM, Sapienza University of Rome, 00161, Rome, Italy; 7Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy; 8Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London, UK
Mitochondrial metabolism reprogramming might enhance metabolic
efficiency. We investigated the ability of the metabolic modulator
trimetazidine (TMZ), which partially inhibits mitochondrial free fatty
acid β-oxidation while enhancing glucose oxidation, to counteract
skeletal muscle dysfunctions and wasting occurring in cancer cachexia.
For this purpose we used mice bearing the C26 coloncarcinoma as a model
of cancer cachexia. Mice received 5 mg/kg TMZ (i.p.) once a day for 12
consecutive days. A forelimb grip strength test was performed, and tibialis anterior and gastrocnemius muscles were excised for analysis. Ex vivo
measurement of skeletal muscle contractile properties was also
performed. Moreover, satellite cells and C2C12 myoblasts were treated
with TMZ during differentiation.
Results: Our data showed
that TMZ induces some effects achieved through exercise, among which is
grip strength increase, an enhanced fast-to-slow myofiber phenotype
shift, reduced glycemia, PGC1α up-regulation, oxidative metabolism and
mitochondrial biogenesis. TMZ also partially restores the myofiber
cross-sectional area in C26-bearing mice, while modulation of autophagy
and apoptosis were excluded as mediators of TMZ effects. Moreover, TMZ
enhances the myogenic potential of skeletal muscle progenitor cells
leading to MyoD, Myogenin, Desmin over-expression and, similarly to
exercise, stimulates the phosphorylation of AMPK and up-regulates PGC1α,
both of which enhancing mitochondrial biogenesis necessary for myoblast
differentiation. Finally, we found that TMZ is able to stimulate
myogenesis in vivo both in the C26 mice model of cancer cachexia and upon cardiotoxin damage.
In conclusion, our data show that TMZ acts like an “exercise mimetic”
and is able to promote myogenesis, enhance regenerative capacity and
trigger some mechanisms of adaptation to stress in cancer cachexia. This
makes the modulation of the metabolism by TMZ a suitable candidate for a
therapeutic rehabilitative protocol design and for
regeneration-impaired disorders, particularly considering that TMZ has
already been approved for clinical use.
Cancer and chemotherapy-induced cachexia yield distinct metabolic perturbations
Fabrizio Pin1,2, Rafael Barreto3, Marion E. Couch4,5,6, Thomas M. O'Connell3,4,5,6 and Andrea Bonetto1,2,3,4,5,6
1Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA; 2Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA; 3Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 4Department of Otolaryngology - Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 5Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA; 6IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, USA
cancer patients frequently suffer from cachexia, a severe wasting
condition characterized by depletion of both muscle and adipose tissue.
Work from our laboratory and others have shown that chemotherapy, one of
the primary treatment options for cancer can also lead to cachexia. In
this study, we employed a comprehensive metabolomics approach to
elucidate the similarities and differences in the metabolic
perturbations of these two drivers of cachexia.
Our study design
included four sets of mice: (1) mice implanted with C26 colorectal tumor
cells, (2) mice given chemotherapy Folfiri (5-FU, leucovorin,
irinotecan) for five weeks, (3) C26 tumor bearing mice treated with
Folfiri, and (4) vehicle treated mice. The multi-platform metabolomics
approach utilized both NMR and mass spectrometry analyses on serum,
muscle and liver tissue. The data highlighted several striking
differences between the metabolic phenotypes of the C26 tumor and
chemotherapy groups. The C26 group displayed reduced levels of TCA cycle
intermediates, branched chain amino acids and short chain
acylcarnitines while those same metabolites were unchanged in the
Folfiri group. The number of low density lipoprotein particles (LDL-P)
increased by more than five-fold in the C26 group while a more modest
two-fold increase was observed in the Folfiri group, suggesting
differences in lipid and cholesterol metabolism. In muscle, the ATP
levels were more significantly reduced in the Folfiri group compared
with the C26 perhaps, suggesting a more dramatic impact on oxidative
metabolism. In the C26 group treated with Folfiri, the effects of each
treatment were sometimes additive and sometimes appeared to be dominated
by one condition over the other.
Overall, our results show that
cancer- and chemotherapy-induced cachexia are characterized by clearly
different metabolic perturbations indicating different
pathophysiological mechanisms. New therapeutic interventions to treat
cachexia will have to account for these differences in order to provide
alterations in sarcoplasmic reticulum and mitochondria are determinants
for loss of mass of fast-twitch fibers in the first stage of
Flávia Alessandra Guarnier1, Fernanda Paschoal Blegniski1, Claudia Pecorai2, Rubens Cecchini1, Feliciano Protasi2 and Simona Boncompagni2
1Dept of General Pathology, Univ. Estadual de Londrina, Londrina, PR, Brazil; 2CeSI-MeT, Center for Research on Ageing and Translational Medicine, Univ. G. d' Annunzio, Chieti, Italy
current literature correlates the proteolysis-related atrophy (which
usually occurs in later stages of cachexia syndrome) to oxidative damage
of proteins. Fast-twitch fibers are more affected during the muscle
waste induced by cancer cachexia. In the present study, we investigated
oxidative modifications, ultrastructural modifications in mitochondria
and sarcoplasmic reticulum (SR), and the correlation with muscle loss in
EDL and Soleus muscles (respectively fast- and slow-twitch muscles) in
pre-cachexia. Male Wistar rats were subcutaneously inoculated with a
suspension of Walker-256 tumor cells and divided into 2 groups:
tumor-bearing rats (T), and tumor-bearing rats treated with
N-acetylcisteine (T-NAC; NAC 1% ad libitum in drinking water), a
drug known to promote increased antioxidant capacity in tissues. After
5 days, pre-cachexia was characterized in T animals according to the
criteria pre-established by Fearon et al. (2011; Lancet Oncol).
Tumor implantation caused decrease in general body weight (−2.77%),
followed by a significant weight loss in EDL muscle (−15.33%),
contrasting with the small mass loss of soleus (−5.14%). We measured
both protein and membrane oxidation and found that only membrane
oxidation was significantly increased in EDL from tumor-bearing mice.
Soleus presented a discrete alteration on redox balance. As a result, we
found that the volume of intracellular membrane organelles such as SR
and mitochondria was significantly decreased (−18.89% and −22.41%,
respectively) compared to group C. In addition, in the EDL of
tumor-bearing rats, the fusion:fission ratio was altered in favor of the
former. Interestingly, all differences were significantly rescued in
T-NAC group, suggesting a central role of oxidative stress in the
modifications of membrane compartments. These data suggests that in
pre-cachectic stages: 1) glycolytic muscles are already more prone to
mass waste, but independently of protein oxidation, and 2) loss of
membrane organelles could play an important role early in these initial
This study was supported by the following grants:
Ciências Sem Fronteiras: CNPq 233892/2014-1 and Brazilian Continuous
Flow Program to support special projects (973/2013) to FAG;
- MIUR Future in Research: RBFR13A20K to SB.
Development of a metabolic biomarker panel for the early detection of cancer cachexia
Rafael Barreto1, Fabrizio Pin2,3, Marion E. Couch3,4,5,6, Andrea Bonetto1,2,3,4,5,6 and Thomas M. O'Connell3,4,5,6
1Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 2Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA; 3Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA; 4Department of Otolaryngology - Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 5Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA; 6IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, USA
Currently, there are no mechanism-based tools for the early detection
& diagnosis of cachexia, a debilitating condition that typically
progresses through three phases, namely, pre-cachexia, cachexia and
refractory cachexia. Unfortunately, the classically emaciated patient is
often in the refractory stage where the decline is irreversible.
In this study we employed a comprehensive, multi-platform metabolomics
including untargeted high field NMR, targeted LC/MS and NMR-based
lipoprotein analysis. Our study design involved implanting mice s.c.
with C26 colorectal tumor cells and sampling serum and muscle tissue
every other day for two weeks. In this model the mice generally develop
significant weight loss starting day 10.
metabolomics analyses of serum revealed that the trajectories of several
biomarkers, among which the branched-chain amino acids (BCAAs),
significantly diverged from controls in advance of detectable weight
loss. In particular, leucine levels significantly dropped by day 6, well
in advance of detectable weight loss and even in advance of a palpable
tumor. Interestingly, previous studies have suggested that reductions in
BCAAs are correlated with increased muscle amino acid oxidation. Other
metabolic markers that diverged at or before day 10 include low density
lipoprotein particles, taurine and GlycA (an inflammatory marker
associated with acute phase response).
initial biomarkers represent a set of critically altered pathways in the
development of cancer cachexia including protein catabolism,
lipolysis/dyslipidemia, oxidative stress and inflammation. This work
provides the foundation for the development of a biomarker panel that
would provide early detection and stratification of cachexia based upon
the unique constellation of metabolic disturbances that may afflict
individual patients. Further studies will be conducted on different
cancer models and eventually in human cohorts.
Doxorubicin induces dose-dependent cachexia in mice
James C. Sorensen1,2, Benjamin M. Butcher1,2, Cara A. Timpani1,2, Alan Hayes1,2,3 and Emma Rybalka1,2,3
1College of Health & Biomedicine, Victoria University, Melbourne, Australia; 2Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, Australia; 3Institute of Sport, Exercise & Active Living (ISEAL), Victoria University, Melbourne, Australia
Introduction: Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent,1 which has emerged as a significant and independent promoter of cachexia during anticancer therapy.2
To characterise its muscle-specific effects, DOX has typically been
administered in cancer-free animal models as a single high bolus dose or
with prolonged periods between dosages.2 However, in the clinical setting, metronomic DOX administration is common since it is generally of greater therapeutic benefit.3
Thus, the aim of our study was to assess the cachectic signature of
metronomic low, moderate and high dose DOX treatment over either one
(short) or two (long) week schedules, in cancer-free mice.
6-week old Balb/C mice were treated with DOX using three different
schedules: (1) 6 × 2mg/kg dosages over 14 days (low-long (LL)); (2)
3 × 4mg/kg dosages over 7 days (moderate-short (MS)); and (3) 6 × 5mg/kg
dosages over 14 days (high-long (HL)). Mice were weighed and body
composition analysis was performed using pre- and post-treatment
EchoMRI. Thereafter, muscles and organs were harvested, weighed and
functional and structural analyses were performed.
DOX treatment induced cachexia in a dose-dependent and
anorexia-independent manner (LL = −14%; MS = −17%;
HL = −28%; p < 0.0005), and this was
mostly attributable to a loss of fat mass (LL = −47%;
MS = −39%; HL = −55%; p < 0.0005). Lean mass wasting was only observed for the HL schedule (−11%; p < 0.05). Regardless of dosage, cachexia was most severe after day 5 of treatment. On the MS schedule, extensor digitorum longus (fast-twitch muscle) mass was reduced by 28% (p < 0.05), while soleus (slow-twitch muscle) mass was unaffected.
Our data highlight that cumulative dosage is more impactful than
treatment duration, but that dose repetition is a factor in cachexia
progression. While overall lean mass was unaffected at lower dosage
schedules, the loss of fast-twitch muscle mass (i.e. EDL) was still
observable, suggesting fibre-type-specific effects which likely account
for the muscle weakness reported by patients.
- Jamieson & Boddy, Expert Opin Drug Metab Toxicol, 2011; 7(10):1201–10.
- Sorensen et al., Cancer Chemother Pharmacol, 2016; 78(4):673–683.
- Scharovsky et al., Current Oncol, 2009;16(2):7.
The systemic activin response to pancreatic tumors: implications for effective cancer cachexia therapy
Zhong, Marianne Pons, Christophe Poirier, Yanlin Jiang, Jianguo Liu,
George E. Sandusky, Yunlong Liu, Guanglong Jiang, Marion Couch, Leonidas
G. Koniaris and Teresa A. Zimmers
Indiana University School of Medicine, Indianapolis, USA
The majority of patients with pancreatic ductal adenocarcinoma (PDAC)
develop cachexia. Serum activin correlates with cachexia and mortality
in PDAC, and Activin over-expression causes cachexia. We studied Activin
expression in PDAC cachexia.
Methods: Data mining, immunohistochemistry, qRT-PCR, cell-based studies, and mouse modeling were used.
In meta-analysis of 9 studies of human PDAC, INHBA, encoding Activin A,
was among the top 1–10% of over-expressed. INHBB, encoding Activin B,
was not. In the pancreas TCGA, high INHBA conferred increased mortality
(HR 1.218, P = 0.003), while INHBB was not significant.
Immunohistochemistry detected Activins in human PDAC in both tumor and
stromal cells. Next, we characterized three novel orthotopic and the
genetic LSL-KrasG12D;LSL-p53R172H;Pdx1-Cre (KPC)
mouse PDAC models. All developed cachexia, with KPC cell lines
expressing more INHBA causing more rapid cachexia. (INHBB was not
detected in cell lines.) Tumors from KPC lines expressed both INHBA and
INHBB, with expression in both tumor and stromal cells. Notably, in both
genetic and orthotopic models, Activin expression was not confined to
tumors. Immunohistochemistry detected Activins in muscle, heart, kidney,
and liver. RT-qPCR indicated that tumors expressed mostly INHBA, while
organs expressed both INHBA and INHBB, with the latter more dynamically
regulated. KPC tumors likely induce Activin and wasting directly,
because KPC cell line conditioned medium-induced INHBA expression and
atrophy in C2C12 myotubes. The Activin trap ACVR2B/Fc showed reduced
efficacy against cachexia in models expressing higher levels of Activin
and did not affect activin expression in organs, suggesting that
circulating Activin was not responsible for systemic Activin expression.
PDAC induces a systemic Activin response. Given the differential
transcriptional regulation of INHBA and INHBB and the differing efficacy
of ACVR2B/Fc on endocrine versus autocrine Activin signaling, our
results suggest that specific targeting and/or upstream targeting of
each tumor-released and tumor-induced Activin would offer more effective
Enhanced β-myosine heavy chain gene expression in rat heart during adjuvant arthritis—a model of cachectic rheumatoid arthritis
Jana Jurcovicova1, Andrea Stofkova2, Viktoria Lory1, Katarina Krskova1 and Stefan Zorad1
of Experimental Endocrinology, Biomedical Centre, Slovak Academy of
Sciences, Bratislava, Slovakia and Department of Normal, Pathological,
and Clinical Physiology, Third Faculty of Medicine, Charles University,
Prague, Czech Republic; 2Department of Normal,
Pathological, and Clinical Physiology, Third Faculty of Medicine,
Charles University, Prague, Czech Republic
Heart failure is a
frequent comorbidity of cachectic rheumatoid arthritis in humans (RA).
Adults with RA have about twofold higher risk of cardiovascular disease
even without enhanced of traditional risk factors. Inflammatory
cytokines are supposed to be implicated in this pathogenesis. Central
role in cardiac heart failure plays β-isoform of myosin heavy chain (β-MHC) by reducing cardiomyocyte contractility. The β-MHC
production is regulated by Foxo1 transcription factor which is
controlled by insulin signaling cascade, and/or by
triiodothyronin-T3/thyroid hormone receptor (TR) complex which
negatively regulates β-MHC transcription.
The aim of our study was to find out whether adjuvant arthritis in rats (AA)—a model of human RA affects cardiac β-MHC expression and to elucidate the mechanisms involved.
was induced to male Lewis rats by complete Freund's adjuvant. On day 18
of maximum inflammatory score the experiment was terminated. The hearts
were perfused in situ with heparinized saline, and the tissues around
left ventricles were dissected and extracted for total RNA. After a
reversed transcription the relative cDNA for each transcript was
measured by real-time PCR using the SYBER green mix and the primer
sequences for rat TNF-α, IL-6, β-MHC, insulin receptor substrates IRS1, IRS2, Foxo1, Foxo4, TRβ1, TRβ2. As reference gene the expression for HPRT was used.
The expression of β-MHC in AA-rats was enhanced against nontreated controls (p < 0.01) and against pair fed rats (p < 0.05).
The cytokine expressions were low at the detection limit. None of the
molecules of the insulin signaling pathway, neither of the Foxo
expressions were changed. However, in AA group the significant
downregulation of TRβ1, TRβ2 was found, indicating desinhibition of β-MHC and thus contributing to its overexpression.
These results show that chronic inflammation during AA may cause cardiac contractility dysfunction by activating of β-MHC expression whereby downregulation of TRs plays a role.
Supported by: grant P34, Czech Republic and grants VEGA 2/0174/17 and APVV-15-0229, Slovak Republic.
in body composition during first cycle of chemotherapy in metastatic
non-small cell lung cancer (NSCLC) are predictive for poor overall
Juliette H.R.J. Degens1†, Karin J.C. Sanders1, Evelyn E.C. de Jong3, Annemie M.W.J. Schols1 and Anne-Marie C. Dingemans2
of Respiratory Medicine, NUTRIM School of Nutrition and Translational
Research in Metabolism, Maastricht University Medical Center,
Maastricht, The Netherlands; 2Department of
Respiratory Medicine, GROW School for Oncology and Developmental
Biology, Maastricht University Medical Center, Maastricht, The
Netherlands; 3Department of Radiation Oncology
(MAASTRO Clinic), GROW School for Oncology and Developmental Biology,
Maastricht University Medical Center, Maastricht, The Netherlands
†Authors contributed equally
Sarcopenia adversely affects prognosis in metastatic NSCLC. However,
the pattern of changes and distribution of muscle- and adipose tissue
mass during chemotherapy and their relation to overall survival (OS) is
unclear. Therefore, we analyzed changes in muscle cross-sectional area
(CSA), intramuscular adipose tissue (IMAT), subcutaneous adipose tissue
(SAT) and visceral adipose tissue (VAT) on CT-images after the first
cycle of chemotherapy.
Methods: In this post-hoc analysis
of the randomized controlled NVALT12 trial (NCT01171170), body
composition was characterized in 117 patients at the third lumbar level
on CT-images obtained before start of treatment and after 1 cycle of
chemotherapy. Changes in body composition were related to OS with Kaplan
Meier and log-rank test. Cox multivariate analysis assessed the
relative contribution of muscle and adipose tissue CSA and distribution
Results: Changes in muscle- and IMAT SCA were an
independent predictor for OS while change in SAT and VAT were not. Three
patterns could be distinguished based on body composition changes;
muscle stable or gain (n = 36, type 1), muscle loss and IMAT stable or gain (n = 47, type 2), muscle- and IMAT loss (n = 34,
type 3). Body composition types were comparable for gender, age,
WHO-PS, TNM-status and comorbidity index. Type 1 was most predictive for
poor OS with a median OS (95% CI) of 8.9 months (5.4 to 12.3) compared
to 10.7 months (6.5 to 14.9) in type 2 (HR 2.1 95% CI (1.3–3.4) p = 0.003). There was no significant difference in OS between type 2 and type 3.
In contrast to previous research in non-pulmonary malignancies, not
only decrease of muscle mass but also IMAT changes are predictive for
poor OS in metastatic NSCLC after one cycle of treatment. Early
recognition of body composition changes could be useful for more
personalised supportive intervention during follow-up treatment.
deficits in baseline cardiac function in NSCLC patients eligible for
carboplatin- based therapy: implications for anti-cachexia clinical
Seyyed Mohammad Reza Kazemi-Bajestani1, Harald Becher2, Charles Butts3, Naveen S. Basappa3, Michael Smylie3, Anil Abraham Joy3, Randeep Sangha3, Andrea Gallivan1, Quincy Chu3 and Vickie Baracos1
1Department of Oncology, Division of Palliative Care Medicine, Cross Cancer Institute, University of Alberta, Edmonton, Canada; 2Department
of Medicine, Division of Cardiology, Alberta Cardiovascular and Stroke
Research Centre, Cross Cancer Institute, University of Alberta,
Edmonton, Canada; 3Department of Oncology, Division of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada
According to European and American regulatory agencies, physical
function (e.g. stair climbing test) would be an approvable (co)primary
endpoint of new anti-cachexia medications; however, it is unknown
whether cardiac function is adequate for physical function tests. We
aimed to explore the cardiac status of a group of patients conforming to
the criteria for inclusion in cachexia clinical trials (i.e., POWER,
ROMANA, and MENAC).
Methods: Seventy patients with
metastatic non-small cell lung carcinoma [51.4% male; 96% ECOG 0–1;
eligible for carboplatin-based therapy] were evaluated before start of
1st line chemotherapy. All of the patients were evaluated by
echocardiography, FACIT fatigue and MRC dyspnea scales. Computed
tomography cross-sectional images were utilized for body composition
Results: In 9 patients (12.8%), echocardiography
revealed previously undiagnosed, clinically relevant cardiac
abnormalities. Seven patients had left ventricular ejection fraction
(LVEF) 32%–47%; 1 patient had severe right ventricular dilation and
pulmonary hypertension, and 1 patient with severe pericardial effusion
warranted hospitalization and drainage. Of these 9 patients, only one
patient had a recent history of heart failure. Ten (14.3%) additional
patients had diastolic dysfunction with preserved LVEF. These cardiac
conditions were associated with worse fatigue (p < 0.05), dyspnea (p < 0.05) and anemia (p = 0.06). Five out of 7 patients with LVEF < 50% were sarcopenic.
A detailed evaluation of the cardiac function in our clinical
trial—eligible population reveals a heterogeneous cardiac profile and
symptom burden that may significantly impact on their ability to perform
physical activities (such as stair climbing), which serve as
anti-cachexia trial endpoints. Cardiac-related inclusion and exclusion
criteria of aforementioned trials would fail to identify these patients.
Detailed echocardiography might need to be included in the screening
procedure of lung cancer patients for clinical trials with anti-cachexia
therapeutics especially those using physical activity as primary
of nutrition disorders in 531 non-small cell lung cancer (NSCLC)
patients: benefit from skeletal muscle mass, anorexia and performance
Hugues Morel1, Didier Debieuvre2, Pierre-Jean Souquet3, Veerle Surmont4, David Planchard5, Franck Bonnetain6, Ivan Krakowski7, Hélène Gaudin8 and Sami Antoun9
1C.H.R. Orléans - La Source, Department of Pneumology, 45067, Orléans, France; 2GHRMSA, Hôpital Emile Muller, Department of Pneumology, Mulhouse, France; 3Centre Hospitalier Lyon Sud, Department of Pneumology, Pierre Bénite, France; 4Gent University Hospital, Department of Thoracic Oncology, Gent, Belgium; 5Institut Gustave Roussy, Department of medical oncology, Villejuif, France; 6CHRU Besançon Jean Minjoz, Methodological and quality of life unit in oncology, Besançon, France; 7Institut
Bergonié, Département Interdisciplinaire de Soins de Support pour le
Patient en Oncologie (DISSPO-CARE), Bordeaux, France; 8Chugai Pharma France, Paris, France; 9Institut Gustave Roussy, Unité de médecine aigue en oncologie, Villejuif, France
An international consensus proposed in 2011 a staging of cancer
cachexia (CAX), mainly based on weight loss (WL), skeletal muscle loss
(SML), inflammation and anorexia (Fearon). While CAX definition relies
on well-defined criteria, those of pre-CAX and refractory CAX remain
imprecise. We initiated this study to refine CAX stages with
Methods: This is a
cross-sectional, prospective, multicentric study conducted in patients
with NSCLC. Skeletal muscle mass (SMM) was assessed by analysing L3
CT-scan images. Patients completed EORTC QLQ-C30 health-related quality
of life (QoL) questionnaire. For pre-CAX stage definition we recorded
anorexia based on patient answer to QoL question on appetite loss. We
defined refractory CAX based on ECOG performance status and WL using the
thresholds values associated with low survival (<5.4 months)
described by Martin. Endpoints were the frequency and the
characteristics of CAX stages.
Results: 531 patients
recruited in 2016 by 56 sites within 3 months were analysed. 312 had SMM
assessment. Median age was 66 years, 79.9% were PS < 2, and the
tumor stage was mainly IIIB-IV (87.3%). 33.8% of patients had pre CAX,
38.7% CAX, and 0.9% refractory CAX. CAX stage progression was associated
with lower functional scale score (except cognitive) of the QoL
questionnaire (p < 0.0001). SMM was the only relevant
criteria found in 8.1% of cachectic patients without WL > 5% and in
43.8% of pre-CAX patients with WL < 2%. Notably, 48.4% of all the
patients and 25.8% of pre-CAX patients had SML with no anorexia
(questioning SML mechanisms not secondary to decreased intake).
This is the first study defining cancer cachectic stages with
quantifiable parameters for pre-CAX and refractory CAX stages. Stage
definitions were supported by associated functional QoL scores. While
measuring SMM is of poor interest when WL is >5%, it could however be
useful for detecting early nutritional disorders.
A longitudinal study of muscle strength and function in patients with cancer cachexia
Nichola Gale1, David Wasley2, Sioned Roberts3, Karianne- Backx2, Annemarie Nelson4, Robert van Deursen1 and Anthony Byrne4
1Cardiff University, School of Healthcare Sciences Cardiff, UK; 2Cardiff Metropolitan University, Cardiff School of Sport, UK; 3Velindre Cancer Centre, Cardiff, UK; 4Marie Curie Palliative Care Research Centre (MCPCRC), Cardiff University, Heath Park, Cardiff, UK
Patients with advancing cancer frequently suffer a reduction in daily
activities with profound effects on function and quality of life
(Laviano et al. 2005).
However, the rate of decline has not been well described in those with
established cancer cachexia (CACS). The aim of this study was to assess
change in muscle strength and physical function over 8 weeks in this
Methods: Patients with lung and
gastrointestinal cancer, with unintentional weight loss of >5% in
6 months or BMI <20 plus 2% weight loss were included. Physical
assessments (baseline, 4 weeks, 8 weeks) included: isometric quadriceps
and hamstring strength, handgrip, standing balance, 10 m walk time and
timed up and go. This was part of a larger study of activity, motivation
and exercise preferences in established CACS.
Results: Fifty patients (32 male), mean ± SD age 65 ± 10 years and BMI 24.9 ± 4.3 kg/m2 were recruited. The majority of patients (n = 43) had a BMI over 20 kg/m2 with 16% of lung patients and 12% of GI patients being underweight (BMI < 19.9 Kg/m2).
Lung cancer patients had lower muscle strength and function than those
with GI cancer (p < 0.05). Despite notable attrition, in the 19 (8
lung and 12 GI) patients who completed all assessments, there was little
change in muscle strength and performance over 8 weeks (p > 0.05). Baseline variables did not differ significantly between completers and non-completers (p > 0.05).
More than a third of patients with established cancer cachexia in our
study were stable over 8 weeks, suggesting a subgroup that may have
potential to benefit from targeted interventions. Better understanding
the physical performance parameters which characterize and differentiate
these patients has important clinical implications for cancer
multidisciplinary team practice.
- 2005. Nat Clin Pract Oncol 2(3), pp. 158–165. et al.
Proteomic profiling of the tumour microenvironment of cachectic patients: the search for biomarkers
Joanna Darck Carola Correia Lima1, Fernanda Janku Cabral2, Estefanía Simões Fernández1, Emídio Marques de Matos-Neto3, Rosangela Santos-Eichler1, José Otoch Pinhata1, Paulo Sérgio Alcantara Martins1, Leo Kei Iwai4, Emer Ferro Suavinho1 and Marília Cerqueira Leite Seelaender1
1University of São Paulo, Brazil; 2University of Campinas; 3University of Piauí; 4Instituto Butantan
Cachexia is a multiorgan syndrome characterised by progressive and
involuntary weight loss and major effects on skeletal muscle. The
pathogenicity and origin of this syndrome is multifactorial and strongly
associated with systemic inflammation due to a complex interaction of
reduced food intake and changes imposed on metabolism by tumour and host
factors. To understand the isolated effects of the tumour
microenvironment, the aim of the present study was to identify changes
in the proteome expression of tumour tissue of cachectic patients and
non-cachectic patients and to investigate possible biological functions
related to these proteins.
Methods: Patients with
colorectal cancer were recruited after signature of the informed consent
form and tumour biopsies were collected in surgery. Patients were
divided into Weight-Stable Cancer (WSC n = 2) and Cachectic Cancer (CC n = 2) groups. Protein was extracted, samples incubated with trypsin and
peptides were isotopically marked with light (D0-TMAB) or heavy
(D3-TMAB). Samples were analyzed by mass spectrometry (LC-MS/MS), and
both quantitation (H/L ratios) and protein/peptide searches in NCBI
databank were done using mascot algorithm. Statistics, proteome
validation and heatmaps for protein expression visualisation were
performed with Perseus. Gene Ontology (GO) analysis was carried out with
Results/Conclusions: In total, 398 proteins were
identified and quantitated. From these, 105 proteins were statistically
significantly different between the groups (p value and false Discovery
rate (FDR) <0.05). Careful analysis of H/L ratio expression on
heatmap was carried out for selection of the proteins that presented
expression profile modulation. 22 proteins were found to be up or
down-regulated by cachexia. GO of these modulated proteins showed that
their majority consisted of proteins related with energetic and protein
metabolism, muscle development and contraction, modulation of immune
response and proliferation, growth and cellular maintenance. In
conclusion, tumours if cachectic patients show a different pattern of
protein expression, implying that one such pattern could be related with
the induction of cachexia. Furthermore, the results provide insight on
the adoption of tumour sample analysis for precocious diagnosis of the
Fatty acid profile alterations in plasma and subcutaneous adipose tissue of cachectic cancer patients
Katrin Radloff1,3, Daniela Mendes dos Reis Riccardi1, Raquel Galvao Figuêredo1, Joanna Darck Carola Correia Lima1, Joyce de Cassia Rosa Jesus-Lima1, Ariene Murari1, José Pinhata Otoch2, Gerhard Paul Püschel3, Alison Colquhoun1 and Marília Seelaender1
1Institute of Biomedical Science, Cancer Metabolism Research Group, University of Sao Paulo, Brazil; 2Department of Clinical Surgery, University of Sao Paulo, Brazil; 3Institute of Nutritional Science, Department of Biochemistry of Nutrition, University of Potsdam, Germany
Systemic inflammation and loss of fat mass are hallmarks of cancer
cachexia. Fatty acids (FA) are involved in inflammatory pathways and the
adipose tissue as storage of bulk FA might contribute to promote
Aim: To assess the FA profile of plasma and
adipose tissue and to measure the gene expression of FA modifying
enzymes in cancer cachexia.
Methods: Volunteers were
recruited after signing the informed consent form at the University
Hospital. Patients subjected to incisional hernia surgery were included
in the control group (Control), while gastrointestinal carcinoma
patients were divided into weight-stable cancer (WSC) group and
cachectic cancer group (CC). Cachexia was diagnosed as in Fearon et al.,
2011. FA were separated and quantified using GC/MS. Gene expression of
FA modifying enzymes of subcutaneous adipose tissue (SAT) were measured
by real-time PCR.
Results: In plasma there was a shift from
unsaturated to saturated FA. The percentage of palmitic acid was higher
in WSC and CC compared to Control (p = 0.006) and stearic acid content was higher in CC (p = 0.025). SAT exhibited slide changes in the bulk fatty acid species. Myristic acid 14:0 was diminished in plasma (p = 0.019) as well as in SAT (p = 0.06).
In plasma, lower contents of different types of n3 and n6-FA were
measured in both cancer groups compared to controls or in CC compared to
WSC. In SAT only 20:2n6 was significantly changed in CC compared to the
other groups (p = 0.04). SAT gene expression of FADS1 and
ELOVL5 that modify long chain FA was not altered while stearoyl-CoA
desaturase expression tended to reduce in cachectic patients (p = 0.08).
Changes in plasma FA profile were different from the changes we
observed in SAT. The enzyme gene expression alone cannot explain the FA
alterations; hence, further studies are needed to understand the FA
profile in cancer cachexia.
randomized feasibility study evaluating an exercise intervention for
patients with advanced GI malignancies and cancer cachexia: trial in
Richard F. Dunne, Supriya Mohile, Jennifer Peckham,
Charles Heckler, Javier Bautista, Michelle Janelsins, Michelle Porto,
Po-Ju Lin, Aram Hezel and Karen M. Mustian
University of Rochester Medical Center, Rochester, 14620, USA
Cancer cachexia (CC) is characterized by progressive loss of weight and
lean muscle mass that contributes to impairments in physical
performance and a poorer prognosis. Although common in gastrointestinal
tract (GI) cancer patients, there are currently no FDA-approved
treatments for CC. Exercise for Cancer Patients (EXCAP©®) is a
home-based, low-to-moderate intensity exercise intervention consisting
of resistance-band training and a tailored walking prescription. We are
currently conducting a randomized controlled feasibility trial
investigating EXCAP©® to improve physical performance and function in
patients with advanced GI malignancies and CC.
Incurable GI cancer patients with >5% weight loss or >2% weight
loss with signs of inflammation (glucose intolerance, anemia, or
hypoalbuminemia) are randomized 1:1 to usual care with chemotherapy (UC)
or a 12-week EXCAP©® regimen beginning on day 1 of chemotherapy
(EXCAP). Subjects undergo physical activity tracking and fitness testing
at baseline, mid-intervention and post-intervention. Cachexia outcome
measures include changes in weight and lean mass via bioelectrical
impedance and computed tomography (CT), cardiorespiratory and muscle
fitness (Short Physical Performance Battery, VO2 max, hand-grip
dynamometry, and muscle activation by EMG), and inflammation and protein
synthesis (C-reactive protein, serum cytokines and branched-chain amino
acids). Since September of 2016, 14 of a planned 40 subjects have
Results: In total, 74% (14 of 19) of patients
offered the study consented to participate. The median age of subjects
is 67.4 years. The EXCAP group increased their daily steps on average by
1400 steps, compared to UC whose average activity declined by 1200
steps. So far, 100% of subjects enjoyed participating “very much.” No
study-related adverse events have occurred to date.
Preliminarily, EXCAP©® is feasible, well-liked and safe in patients
with CC. The trial is currently enrolling; additional subjects are
needed to determine whether exercise can impact physical performance and
muscle mass in CC.
Using body composition from expedient image analysis to predict energy needs in cancer
Sarah A. Purcell1, Vickie E. Baracos2, Jessica R. Lieffers3, Sunita Ghosh2, Marina Mourtzakis4 and Carla M. Prado1
of Agricultural, Food, and Nutritional Science, Faculty of
Agricultural, Life, and Environmental Sciences, University of Alberta; 2Department of Oncology, University of Alberta; 3College of Pharmacy and Nutrition, University of Saskatchewan; 4Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo
Resting energy expenditure (REE) is variable in cancer and influences
energy needs. We assessed the agreement between measured REE (mREE) and
predicted REE (pREE) using anthropometric/demographic variables and
skeletal muscle and total adipose cross-sectional area (CSA, cm2).
Patients with advanced colorectal cancer were recruited from the Cross
Cancer Institute (Edmonton, Canada). REE was measured by indirect
calorimetry. CSAs were quantified via CT images at the 3rd lumbar
vertebrae using Slice-O-Matic, V4.3. Multiple linear regression
identified the contribution of age, sex, height, weight, skeletal muscle
and total adipose tissue CSAs to REE and generated equations using
significant (p < 0.05) variables. Accuracy of new equations
was compared to the Harris–Benedict equation. mREE was compared to
predicted using Lin's concordance and Bland–Altman analyses.
Results: 24 patients were included (BMI 26.1 ± 5.3 kg/m2;
age 59 ± 13y); mean mREE was 1502 ± 306 kcal/day. Average pREE from the
Harris–Benedict equation was 1542 ± 312 kcal/day; bias = 41 kcal/day;
limits of agreement = −212 to 293 kcal/day. Linear regression Model 1
included age, sex, height, and body weight; age (p < 0.001), height (p = 0.001), and weight (p < 0.001) were predictors of REE (p < 0.001 R2 = 0.870,
SEE = 118 kcal/day). Mean pREE from this model was 1502 ± 285 kcal/day;
bias = 0 kcal/day; limits of agreement = 216 to 216 kcal/day. In Model
2, skeletal muscle and total adipose tissue CSA were added. Skeletal
muscle (p = 0.006), age (p < 0.001), weight (p = 0.009), and height (p = 0.014) were predictors of REE (p < 0.001, R2 = 0.914,
SEE = 99 kcal/day). Mean pREE was 1505 ± 290 kcal/day;
bias = 3 kcal/day; limits of agreement = −186 to 173 kcal/day. Lin's
concordance coefficient was highest for Model 2 equation with a
“substantial” strength of agreement (ρc = 0.958). Model 1 (ρc = 0.9304) and Harris–Benedict (ρc = 0.905) equations had “moderate” agreement.
Conclusions: Skeletal muscle is a better predictor of REE on an individual and group level compared to anthropometric/demographic data.
ectopic fat in skeletal muscle and liver is associated with shorter
survival in patients with colorectal liver metastases
David P.J. van Dijk1,2, Junfang Zhao1,2, Katrin Kemter1,2, Vickie E. Baracos3, Cornelis H.C. Dejong1,2,4,5, Sander S. Rensen1,2 and Steven W.M. Olde Damink1,2,4,5
1Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands; 2NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, The Netherlands; 3Department of Oncology, University of Alberta, Edmonton, Canada; 4GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; 5Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
Adipose tissue and skeletal muscle mass have been studied extensively
in patients with cancer (cachexia). While increased adipose tissue is
associated with longer survival, it has been suggested that increased
ectopic fat in the muscle and liver is related to poor survival. Using
multiple computed tomography scans (CT-scans) over time and liver
biopsies, we assessed the relationship between survival and liver
steatosis as well as preoperative changes in muscle fat content and body
composition in patients with colorectal liver metastases.
Patients with two available preoperative CT scans were selected from a
cohort of 289 consecutive patients with colorectal liver metastases
undergoing partial hepatectomy. Scans were analysed using a single CT
slice at the L3 level to assess adipose tissue mass and skeletal muscle
mass. Muscle fat content was assessed by calculating the average
Hounsfield units of the muscle tissue at L3 level (radiation
attenuation). Liver biopsies were histologically scored for steatosis
using the SAF score.
Results: One hundred and thirty-seven
patients had two available preoperative CT scans with a mean time
interval of 3.2 months. In multivariate cox-regression analysis,
reduction in muscle radiation attenuation, reflecting fat accumulation,
was associated with shorter disease-free survival (HR 1.98, 95%-CI:
1.20–3.28; p < 0.01) and shorter overall survival (HR 1.79,
95%-CI: 1.12–2.86; p = 0.01). Liver steatosis was also associated with
shorter overall survival (HR 1.77, 95%-CI: 1.07–2.90, p = 0.03).
In contrast, high baseline total adipose tissue mass was related to
increased disease-free survival (HR 0.60, 95%-CI: 0.45–0.80; p < 0.01) and overall survival (HR 0.75, 95%-CI: 0.58–0.98, p = 0.03). Changes in skeletal muscle mass were not significantly associated with survival.
Ectopic fat accumulation in muscle and liver was associated with
shorter disease-free survival and overall survival, while high total
adipose tissue mass seemed to be protective. This indicates that ectopic
fat may be an important marker of tumour progression.
Conditioned medium from cachectic pancreatic tumor organoids inhibits the contractile smooth muscle cell phenotype
Rianne D.W. Vaes, David P.J. van Dijk, Steven W.M. Olde Damink and Sander S. Rensen
of Surgery and NUTRIM School of Nutrition and Translational Research in
Metabolism, Maastricht University, Maastricht, The Netherlands
Pancreatic cancer patients often suffer from gastrointestinal-related
symptoms which may be the consequence of underlying gastrointestinal
motility problems (e.g. gastroparesis). Although muscle loss in
cachectic pancreatic cancer patients is most obvious in skeletal muscle,
these clinical symptoms suggest that cachexia manifest itself also in
smooth muscle, a tissue responsible for the contractile functionality of
the gastrointestinal tract. We therefore aimed to investigate whether
factors secreted by pancreatic tumor cells from cachectic or
non-cachectic individuals affect the smooth muscle cell (SMC)
Methods: 3D pancreatic tumor organoids were established from pancreatic tumor tissue, obtained from pancreatic cancer patients (n = 3)
of whom the degree of cachexia was thoroughly assessed (weight loss,
systemic inflammation, handgrip strength, etc.). Simultaneously, human
visceral SMCs were grown to confluency on basement membrane matrix
coated surfaces and kept for up to 6 days in the presence of 2% serum
allowing SMCs to acquire a contractile phenotype. After 6 days, SMCs
were exposed to 25% organoid conditioned medium (CM) for 24 h. mRNA
expression of specific contractile SMC markers (Acta2, Actg2, Tagln, Smtn) and extracellular matrix components (Col1a1, Col3a1, Eln) was analyzed by RT-qPCR.
Results: CM from cachectic pancreatic tumor organoids provoked decreased expression of Acta2 (α-smooth muscle actin; 1.20-fold) and Actg2 (γ-smooth muscle actin; 1.92-fold), indicating loss of the mature contractile phenotype. Concurrently, we observed increased expression of elastin (Eln;
3.4-fold) supporting a shift from the contractile towards the so-called
synthetic phenotype. Organoids established from non-cachectic patients (n = 2)
did not significantly affect expression of these contractile and
synthetic markers. Experiments with organoid CM from 8 additional
patients are ongoing, as are proteomics analyses to identify potential
organoid-secreted factors involved.
pilot data suggest that pancreatic tumor cells from cachectic patients
secrete factors that diminish the contractile SMC phenotype, potentially
contributing to gastrointestinal motility problems.
Role of Electrogastrography (EGG) and effect of ginger (Zingiber Officinale Roscoe) on gastrointestinal symptoms and inflammatory markers in patients with cancer cachexia
Ravi Bhargava and Martin Chasen
Bruyère Continuing Care - Bruyère Research Institute, Ottawa, Canada
Electrogastrography (EGG) is a non-invasive method for the measurement
of gastric myoelectrical activity (GMA). The aromatic, spasmolytic and
carminative properties of ginger suggest it has direct effects on the
GMA. Cancer cachexia is associated with a variety of gastrointestinal
symptoms such as nausea and vomiting. There are no data on pattern of
GMA in response to Ginger in patients with cancer cachexia. Objective of
this study is to determine (1) role of electrogastrography in patients
with cancer cachexia, (2) effect of oral Ginger administration on GMA in
patients with cachexia, and (3) to evaluate GI symptoms using Edmonton
symptom assessment scale (ESAS), patient-generated subjective global
assessment form (PGSGA), dyspepsia symptom severity index (DSSI) and
correlate levels of inflammatory markers and Ghrelin.
Patients with Cancer cachexia were recruited to document a baseline and
post water load EGG after oral ingestion of Ginger capsule (1650 mg)
once daily, for 14 days. DSSI, ESAS and PGSGA were completed, and blood
test to measure Ghrelin and inflammatory markers was done pre and post
Results: Fifteen participants (8M; 7F) with a
median age of 58 and varying cancer diagnoses were enrolled. EGG
diagnosis showed that 9 of the 15 patients had a direct improvement in
their GMA. All enrolled subjects showed statistically significant
improvement in nausea, dysmotility-like symptoms and reflux-like
symptoms. There was no correlation found for ginger administration and
Conclusions: Electrogastrography has
shown that Gastric myoelectrical activity may get impaired in patients
with cancer cachexia. By regulating gastric motility, ginger may improve
a range of GI symptoms that can affect oral intake and quality of life.
Cachexia in lymphoma patients: preliminary results of prevalence and risk factors
Joris Mallard1, Cédric Baudinet1,2,3, Manuel Gaviria1, Aline Herbinet1, Ghislain Quai1, Tarik Kanouni2, Pierre Louis Bernard3 and Guillaume Cartron2
1V@Si SAS, R&D unit, University of Montpellier, 93 Plan de la Prairie, 34270 Saint-Mathieu-de-Tréviers, France, vas-i.fr; 2Montpellier University Hospital, Clinical Hematology clinic, 80 Avenue Augustin Fliche34090, Montpellier, France; 3Euromov, University of Montpellier, 700 Avenue du Pic Saint-Loup 34090, Montpellier, France
Cachexia is a major cancer comorbidity defined as a multifactorial
syndrome characterised by an ongoing loss of skeletal muscle mass and
high mortality. Inflammation with C-Reactive Protein (CRP) level
increase is one of the cachexia mechanisms. Age, gender and Body Mass
Index (BMI) represent risk factors of skeletal muscle loss. Lymphoma is a
hematological cancer and includes non-Hodgkin and Hodgkin lymphoma. No
recent studies substantiate cachexia prevalence regardless of lymphoma
type or analyze risk factors. This retrospective study aims to describe
cachexia prevalence in non-Hodgkin and Hodgkin lymphomas and to analyze
association of cachexia with inflammation, age, gender and BMI.
Weight loss was calculated from start of chemotherapy (M0) to 6 months
later (M6). Cachexia was diagnosed if weight loss was greater than 5% of
total body weight over past 6 months (Fearon's definition, 2011).
Correlation between weight loss and inflammation at M6 was investigated
using CRP. Risk factors analyzed were age, gender, and BMI.
100 patients were included comprising 59 men and 41 women (mean age
62). The cachexia prevalence was 39%, in both men and women. CRP levels
were significantly higher in patients with cachexia (p < 0.01).
At M6, mean CRP levels of cachectic patients were significantly higher
than the 5 mg/L threshold of inflammation in Evan's definition (p < 0.01). There was a weak positive correlation between weight loss and respectively CRP level at M6 (r2 = 0.42), age (r2 = 0.12) and BMI (r2 = 0.04).
Cachexia prevalence was 39% in lymphoma patients. Inflammation, age,
gender and BMI do not seem to be relevant risk factors. Since cachexia
prevention concerns all lymphoma patients, exercise could represent one
way to prevent it since diagnosis, by increasing protein synthesis and
muscle hypertrophy. A study assessing effect of exercise on cachexia
prevalence in lymphoma patients will follow these preliminary results.
Timed up and go test better explains high-density muscle mass in gynecological cancer patients
Regielly Candido Silva1, Gabriella Villaça Chaves2, Anke Bergmann1 and Fernando Tadeu Trevisan Frajacomo1
1Program of Molecular Carcinogenesis, Brazilian National Cancer Institute, Rio de Janeiro, Brazil; 2Department of Nutrition and Dietetics, Brazilian National Cancer Institute, Rio de Janeiro, Brazil
Background and aims:
Current studies recognize muscle quality, means high-radiodensity
skeletal muscle index (HRSMI), as a powerful and independent variable to
predict prognosis in cancer survivors. However, it is not clear if
muscle quality attenuation on computed tomography (CT) imaging may
overcome into lower muscle function. This cross-sectional observational
study investigated whether HRSMI is associated with muscle function in
gynecological clinical oncology.
Methods: Patients with
gynecological cancer prior to treatment were invited to participate. CT
images at the third lumbar vertebra (L3) were used to assess overall
skeletal muscle index (SMI), calculated in the range −29 to +150
Hounsfield units (HU). The skeletal muscle attenuation in the range +30
to +150 HU was denominated HRSMI. To assess muscle function, we included
handgrip dynamometer (HGS/kg), arm curl/30 sec, sit-to-stand/30 sec,
sit-and-reach/cm and Timed-up and go (TUG, sec) test.
Of 73 patients included, mean ages 51.22 (SD ± 14.29), 60.3% had
cervical cancer diagnosis. After controlling for BMI, age and cancer
stages, we found no evidence of association between SMI and muscle
functional impairment. However, considering HRSMI, it was associated
with higher values of HGS (p = 0.003), arm curl (p = 0.002), sit-to-stand (p = 0.038), and TUG (p < 0.001).
Specifically, adjusted linear regression model retained TUG test as the
most sensitive to decode HRSMI in gynecological cancer (β = −1.45, p = 0.003, R2 = 38%).
Further, ROC analysis indicated an optimal cut-point value of 6.48 sec
to TUG (77% sensitivity and 75% specificity) discriminating those
individuals in the 3rd quartile of HRSMI.
study reinforced relevance of muscle quality, rather than muscle
quantity, in the oncology setting. In fact, solely, HRSMI was associated
with higher functional capacity. Further, our findings suggest TUG test
is eligible as candidate biomarker to elucidate changes in muscle
quality in gynecological cancer patients.
Disease-related malnutrition factors in patients with ulcerative colitis
Sergei Ivanov1, Igor Khoroshilov2, Yury Uspenskiy1,3 and Yulia Fominikh1
1Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation; 2North-Western State Medical University named after I.I. Mechnikov, St. Petersburg, Russian Federation; 3Saint-Petersburg State Pediatric Medical University, St. Petersburg, Russian Federation
Underweight is a frequent complication of ulcerative colitis (UC), but
it is not always clear what effect disease-related malnutrition itself.
Our objective is to assess relationship between the disease-associated
factors and the undernutrition occurrence in UC patients.
Cross-sectional retrospective analysis included data of 103 patients
with UC. Demographic characteristics (sex and age), disease behavior
(relapse, remission), the extent of colonic involvement
(proctitis/left-sided colitis or pancolitis), the total number of
relapses since the onset of the disease were analyzed. Underweight was
taken into account when the patient's body mass index was less than
18.5 kg/m2, according to WHO criteria. A binary logistic
regression was performed to assess the relationship between
disease-related factors and the undernutrition occurrence, taking into
account demographic characteristics. The adjusted model included the
patient's age, disease behavior, the extent of colonic involvement and
the total count of relapses.
Results: The general
prevalence of underweight among patients with UC was 16.5%. Pancolitis
and female sex were associated with a higher incidence of underweight in
the adjusted binary logistic model: OR 7.0 (95% CI: 1.3–38.5) and 5.7
(95% CI: 1.3–24.9), respectively. However, there was no reliable
relationship between others disease-related factors and the incidence of
undernutrition in patients with UC.
results of this study may be of great importance for screening and
preventing of the undernutrition in UC patients with pancolitis.
protein, leucine and fish oil-supplemented nutrition attenuates right
ventricular fibrosis and skeletal muscle atrophy in mice with cardiac
Paulien Vinke1,2, T. Scott Bowen, Renger F. Witkamp2 and Volker Adams1† and Klaske van Norren2†
1Department of Internal Medicine and Cardiology, Leipzig University—Heart Center, Leipzig, Germany; 2Nutrition and Pharmacology Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
Cardiac cachexia is characterized by ventricular remodeling that is
associated with skeletal muscle wasting. However, therapeutic strategies
that target both cardiac and skeletal muscle in order to prevent
maladaptations remain sparse. The present study administered a standard
chow supplemented with high protein, leucine, fish oil and
oligosaccharides, to determine whether cardiac and skeletal muscle
remodeling could be attenuated during cardiac cachexia.
Methods: Female mice (C57/BL6) were treated for 8 weeks with saline (sham; n = 10)
or monocrotaline (MCT; 600 mg/kg; n = 10) to induce cardiac cachexia in
combination with a control diet (standard chow AIN-93 M), while a
further MCT-treated group received supplemented nutrition (NS,
isocaloric) (MCT + NS; n = 10). Subsequent histological analyses were
performed in the right ventricle and tibialis anterior and microarray
analysis was performed for the right ventricle.
Results: Compared to sham mice, relative body weight was impaired (p < 0.05)
in MCT and MCT + NS by 5%. Compared to shams, MCT mice also showed an
increase in heart weight, right ventricular thickness and fibrosis (all
p < 0.05); however, these alterations were attenuated in MCT + NS
mice. Subsequent Gene Set Enrichment Analysis of the right ventricle
confirmed upregulation in fibrotic pathways in the MCT—compared to
sham-treated mice (P < 0.05), which were downregulated in
the MCT + NS mice. In addition, skeletal muscle fiber cross-sectional
area was reduced (P < 0.05) by 22% in MCT compared to sham mice, but
preserved in the MCT + NS group (1178 vs 1503 vs 1495 μm2,
respectively), with protein expression of the key E3 ligase MuRF1 also
reduced by 30% compared to MCT mice alone (p < 0.05).
A multi-compound supplemented nutrition significantly attenuated both
right ventricular and skeletal muscle maladaptations in a mouse model of
cardiac cachexia. These data may provide a novel therapeutic strategy
for combating pathophysiological alterations in cardiac cachexia.
of serum amino acids among community dwelling older adults from Hong
Kong MrOs and MsOs cohort study: special reference to sarcopenia
Liu-Ying Zhu1, Ruth Chan1, Jason Leung2, Timothy Kwok1,2 and Jean Woo1
1Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR; 2Jockey Club Centre for Osteoporosis Care and Control, The Chinese University of Hong Kong, Hong Kong SAR
The availability of blood amino acids, especially the essential amino
acids (EAAs) is the potent stimulus for muscle protein synthesis. We
aimed to compare the profile of serum amino acids among sarcopenic and
non-sarcopenic community dwelling older adults from Hong Kong MrOs and
MsOs cohort study.
Methods: Baseline data of 2997 Chinese
adults aged >65 of Mr and Ms Os (Hong Kong) Cohort Study were
analyzed. Sarcopenia was defined using the Asian Working Group Criteria.
Serum amino acids levels (EAAs including valine, leucine, isoleucine,
methionine, phenylalanine, tryptophan and non-EAAs including glutamine,
arginine, proline, etc.) were measured. Statistical analyses were
performed separately for male and female.
Results: Mean age of the entire sample was 71.9 years old and 47.5% was male. There were 156 (5.2%) subjects (male n = 91, female n = 65)
being defined to have sarcopenia. Serum levels of all amino acids of
both sarcopenic and non-sarcopenic groups met the requirement for adults
above 18-year-old. When compared to non-sarcopenic men, men with
sarcopenia showed significantly lower serum levels of branched-chain
amino acids (leucine, isoleucine and valine p < 0.0001), methionine (p < 0.01), tryptophan (p < 0.01), proline (p = 0.039) and tyrosine (p = 0.016).
In contrast, women with sarcopenia only showed lower levels of
glutamine, glutamic acid, leucine and valine (p < 0.05)
than women without sarcopenia, whereas no significant difference in
other amino acids was observed between the two groups. After adjusting
for age, body mass index, physical activity scale for the elderly,
energy intake and instrumental activities of daily living impairment,
only glutamine (p = 0.045) and homocysteine (p = 0.031) in male and tyrosine (p = 0.004) in female showed significant difference between sarcopenic and non-sarcopenic subjects.
The role of amino acid and the effectiveness of AAs supplements may
need further exploration with prospective randomized controlled trials
for sarcopenic elderly.
nutritional and pharmacological interventions targeting chronic
low-grade inflammation in middle-aged and older adults: a systematic
review and meta-analysis
Carlo Custodero1,2, Robert T. Mankowski1, Stephanie A. Lee1,3, Todd M. Manini1, Marco Pahor1 and Stephen D. Anton1
1Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; 2U.O.C.
Medicina Interna Universitaria “C. Frugoni”, Dipartimento
Interdisciplinare di Medicina (DIM), University of Bari “Aldo Moro”,
Italy; 3Department of Public Health, Social and
Behavioral Sciences, Clinical and Translational Science, University of
Florida, Gainesville, FL, USA
low-grade inflammation could be one of the mechanisms underlying the
aging process. Interleukin (IL)-6 and C-reactive protein (CRP),
well-recognized markers of this condition, are positively associated
with impaired physical performance, frailty, sarcopenia and higher
mortality. To date, few interventions have been identified to reduce
chronic systemic inflammation and improve functional performance in
seniors. Thus, the purpose of this review was to examine the state of
evidence from relevant randomized controlled trials on the effects of
nutritional and pharmaceutical compounds on established markers of
inflammation in middle-aged and older adults.
systematic literature search was conducted in MEDLINE, PubMed and EMBASE
databases using combinations of the target compounds which are
promising, safe, affordable, acceptable, and practical (omega-3,
resveratrol, vitamin D, probiotics, Angiotensin Receptor Blockers
[ARBs], metformin) with “inflammation” OR “c-reactive protein” OR
“interleukin-6.” To be included, studies were limited to randomized
controlled trials with placebo or control group receiving no treatment.
Other key inclusion criteria were participants 45 years and older with
chronic low-grade inflammation as defined by IL-6 levels between 2.5 and
30 pg/ml and/or CRP levels between 2 and 10 mg/L.
Overall, 49 of 858 studies fulfilled the selection criteria. For IL-6,
the following compounds showed a significant effect compared to placebo:
probiotics (−0.68 pg/ml), ARBs (−0.37 pg/ml) and omega-3 (−0.19 pg/ml)
(Table 1 and Figure 1).
For CRP, a significant reduction was observed with probiotics
(−0.43 mg/L), ARBs (−0.2 mg/L), omega-3 (−0.17 mg/L) and metformin
(−0.16 mg/L) (Table 1 and Figure 2).
These results provide support for the potential of some nutritional and
pharmaceutical compounds to significantly reduce established markers of
systemic inflammation in middle-age and older adults. Specifically,
interventions utilizing probiotics, ARBs and omega-3 produced
significant reductions in IL-6 levels, and interventions utilizing
probiotics, ARBs, omega-3 and metformin produced significant reductions
Nutritional and functional status in survival of free-living mild Alzheimer's disease patients
Odete V. Sousa1,2,3 and Teresa F. Amaral1,4
1Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Porto, Portugal; 2UNIFAI - Instituo de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal; 3Hospital de Magalhães Lemos E.P.E, Porto, Portugal; 4UISPA – LAETA / INEGI, Faculdade de Engenharia, Universidade do Porto, Porto, Portugal
Nutritional status may be a modifiable factor in the progression of
dementia. Moreover, dementia is an important cause of mortality, and
nutritional status on prognosis and survival will be of interest to
health and social care. A decline of nutritional and functional status
is very common in the end stages of Alzheimer's Disease (AD). The aim of
this study was to quantify the association between nutritional and
functional status in survival of free-living mild AD patients`.
A prospective observational study was conducted in 79 free-living mild
AD patients (32 men; age: 78.2 ± 6.6 years) between 2012 and 2017.
Nutrition status was evaluated with body mass index (BMI) WHO cutoffs,
FFM index ESPEN 2016 cutoffs, MNA full-form score and bioimpedance
analysis. Sarcopenia was defined according to EWGSOP 2010 criteria.
Functional status using gait speed (GS) and handgrip strength (HGS) was
determined. Kaplan–Meier and adjusted Cox proportional hazard ratio (HR)
methods were applied.
Results: Among the 79 participants,
20 (25.3%) died during follow-up (mean follow-up period was
70.5 months). Forty-one participants (51.9%) were underweight, 29.1%
overweight/obesity and the remaining was at normal weight. Mortality
risk was increased in underweight (HR: 3.29; 95%CI: 1.17–9.28; p = 0.024)
compared to normal-weight and overweight-obese participants. HGS tercis
(first [lowest]: HR: 4.26; 95%CI: 1.18–15.30; p = 0.026), low GS (HR: 2.70; 95%CI: 1.10–6.62; p = 0.029), low phase angle (HR: 2.51; 95%CI: 1.02–6.15; p = 0.044), undernutrition evaluated by MNA (HR: 4.77; 95%CI: 1.72–13.21; p = 0.003) and weight loss (HR: 2.92; 95%CI: 1.12–7.60; p = 0.028)
increased the mortality risk. Underweight by BMI and, low muscle
function by GS, were independently associated with higher probability of
non-survival (HRs of 3.65: 95%CI: 1.29–10.35; p = 0.015, and 2.85: 95%CI: 1.14–7.10; p = 0.024, respectively).
Conclusions: Underweight and low muscle function were associated with lower probability of survival in free-living AD patients.
between phosphatase and tensin homologue (PTEN) expression, calories
supplemented and glucose control in young trauma patients
Alessio Molfino1, Maria Ida Amabile1, Francesco Alessandri2, Alessio Farcomeni3, Paola Mosillo4, Donatella Dell'Utri2, Maurizio Muscaritoli1, Filippo Rossi Fanelli1 and Alessandro Laviano1
1Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; 2Department
of Cardiovascular, Respiratory, Nephrology, Anesthesiology and
Geriatric Sciences, Sapienza University of Rome, Rome, Italy; 3Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy; 4Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
PTEN reduces insulin sensitivity and its expression increases during
sepsis. Considering that critically ill patients present insulin
resistance, we investigated the role of PTEN expression on glucose
control and clinical outcome(s) in young adult patients hospitalized for
trauma in an intensive care unit (ICU) receiving artificial nutrition.
This was an observational, single-center study. Plasma glucose levels
and its variability were recorded in patients. PTEN expression via
western blotting analysis was measured, and the associations between
PTEN, plasma glucose levels and glycemic variability, and calories
administered were investigated. Parametric and non-parametric tests were
performed, as appropriate, and P < 0.05 was considered statistically significant.
Twenty patients (13 men, mean age of 37.3 ± 12.7 years) were
considered. No correlation between plasma glucose and PTEN was
documented (r = −0.15, P = 0.55), neither between glycemic variability and PTEN expression (r = −0.00, P = 0.99). However, total kcal/day administered and PTEN expression significantly correlated (r = 0.56, P = 0.01).
Also, patients with PTEN levels below the median value received less
kcal/day than those with PTEN above the median (P = 0.048). This association was more pronounced when adjusted for body weight (P = 0.03) and for the average of insulin daily administered (P = 0.02).
Conclusions: PTEN expression might contribute to glucose homeostasis and disposal in critically ill patients receiving artificial nutrition.
- NICE-SUGAR Study Investigators. N Engl J Med 2009
- Diabetes Metab 2016, et al.
- Nat Rev Endocrinol 2010, et al.
- Mol Cell Biol 2006, et al.
- N Engl J Med 2006, et al.
study to identify the modification of performance in sarcopenic nursing
home patients after introduction of protein and D vitamin
Milko Zanini1, Annamaria Bagnasco1, Gianluca Catania1, Giuseppe Aleo1, Stefania Ripamonti2, Davide Gonella1, Michela Barisone1, Nicoletta Dasso1 and Loredana Sasso1
1Department of Health Sciences Univeristy of Genova, Italy; 2Private Outpatient Nutritional Service, Brugherio, MB, Italy
In the population between 60 and 70 years prevalence, ratio is from 5
to 13% and in more than 80 year old people the prevalence is between 11
and 50% .
European Working Group on Sarcopenia in Older People (EWGSOP) defined a
conceptual framework that shows three level of sarcopenia:
pre-sarcopenia, sarcopenia and high sarcopenia.
indicate that a vitamin D and leucine-enriched whey protein oral
nutritional supplement can improve in muscle mass, and lower-extremity
function among sarcopenic older adults .
To improve the management of sarcopenic patients in the province of
Genoa (IT) and to measure the prevalence of sarcopenia in elderly
institutionalised in Genoa using the EWGSOP-defined algorithm.
Methods: Transversal, prospective observational study in nursing homes.
criteria: active tumoral disease; severe cognitive impairment;
condition against bioimdenziometric analysis. Sarcopenia has been
evaluated with the definition and EWGSOP-defined algorithm physical
performance: gait speed of using the 4-meter walking; hand grip strength
test using Dynax digital dynamometer and evaluation of Skeletal Muscle
Index (SMI) using BIA vector analysis.
Results: In this
pilot, we test 17 people from 2 different nursing homes; we found all 17
patient enrolled at high-level sarcopenia. During observation, the
patients were supplemented with Leucine and Vitamin D with by the
nursing home physicians. We provide the same test after three months of
therapy, and we found a light modification on EWGSOP indicators as shown
in Table 1.
The improvement of EWGSOP parameter, even not significant, allow us to
be confident in developing the next RCT to assess parameters in a larger
sample of patients.
- 1Sarcopenia: European consensus on definition and diagnosis. Age Ageing 2010, 39(April):412–423, , , , , , , , , , , , :
- 2and others. "Effects
of a vitamin D and leucine-enriched whey protein nutritional supplement
on measures of sarcopenia in older adults, the PROVIDE study: a
randomized, double-blind, placebo-controlled trial." J Am Med Dir Assoc 16, no. 9 (2015): doi:https://doi.org/10.1016/j.jamda.2015.05.021, , , , , , ,
Effect of the underlying renal disease on metabolic and nutritional parameters in older adults with reduced renal function
Alessio Molfino1, Silvia Lai1, Maria Ida Amabile1, Silvia Altieri2, Daniela Mastroluca3, Carlo Lai4, Paola Aceto5, Massimiliano Crudo6, Filippo Rossi Fanelli1 and Maurizio Muscaritoli1
1Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy; 2Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy; 3Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy; 4Department of Dynamic and Clinic Psychology, Sapienza University of Rome, Rome, Italy; 5Department of Anesthesiology and Intensive care, Catholic University of Sacred Heart, Rome, Italy; 6Software House INTECS S.p.A, Rome, Italy
Chronic kidney disease (CKD) is highly prevalent among older adults.
Increased risk of cardiovascular disease is frequent in renal
impairment, and metabolic and nutritional derangements are associated
with CKD. We compared the metabolic, nutritional, and cardiovascular
impact of reduced renal function between patients with and without known
Methods: Consecutive outpatients aged
≥65 years with reduced renal function were enrolled and divided into 2
groups: Group A (patients with history of renal disease) and Group B
(patients with unknown renal disease). Nutritional and metabolic
parameters, including involuntary body weight loss (BWL) in the previous
6 months, mineral metabolism, inflammatory indices, and left
ventricular mass index (LVMI), were determined. Parametric and
non-parametric tests were performed as appropriate, and P < 0.05 was considered statistically significant.
Results: Seventy-six patients were enrolled. Group A (n = 39,
M: 24) showed greater BWL with a significant reduction of
25-hydroxyvitamin D, transferrin, cholinesterase, albumin, and greater
LVMI with respect to Group B (P < 0.01). In addition, Group A
showed significantly increased intact parathyroid hormone, total
cholesterol, low-density lipoprotein, triglycerides, and C-reactive
protein when compared to Group B (P < 0.05).
The positive history of renal disease may negatively impact on several
nutritional and metabolic parameters related to increased cardiovascular
risk among older adults.
- Nephron Clin Pract 2010, et al.
- Curr Opin Clin Nutr Metab Care 2009, et al.
- Ren Fail 2014, et al.
- J Cachexia Sarcopenia Muscle 2014, et al.
obese and malnutrition risk are associated to low survival in a cohort
of chronic heart failure patients independently
Sheila Molinero-Abad1,2,3, María Soto-Célix4, Leticia Sánchez Gómez1,2, Ana Riego-Valledor1,2 and Alberto Mijan-de-la-Torre1,2,3
Medicine, Clinical Nutrition Unit, Hospital Universitario de Burgos,
Burgos, Faculty of Medicine, University of Valladolid, Valladolid,
Spain; 2Clinical Nutrition Unit, Hospital Universitario de Burgos, Burgos; 3Faculty of Medicine, University of Valladolid, Valladolid, Spain; 4Clinical Nutrition Unit, Universidad Pontificia Católica de Chile, Santiago de Chile, Chile
Our previous studies have shown how Sarcopenia is a prevalent syndrome
in CHF patients with a lower survival and malnutrition risk modifies
survival in this setting too. Sarcopenic Obese account for a significant
share. Now we wanted to check if sarcopenic obese modifies survival and
his association with malnutrition risk.
Methods: Prospective cohort study (n = 103)
patients with CHF (NYHA III-IV) were consecutively selected. Nutrition
risk screening (NRS-2002), Mini-Nutritional assesment (MNA) and
Subjective global assessment (VGS) were performed. Muscle function was
measured by hand-grip dynamometry (kg)- lower limit <20(f);
<30(m)-. Appendiceal mass index and fat mass index were calculated
(DUAL Energy-X-RayAbsorciometry (DXA)) and cut-off values for Sarcopenia
were set according to Rosetta Study. Sarcopenic Obese was set according
Baumgartner study Patients were followed-up and survival rate (months)
registered. Data were stat analyzed by Kaplan–Meier, Log-Rank Tests and
Chi-squared test. Statistical significance was reached at p < 0.05.
One-hundred three patients (50f, 82.5y; 53m, 82.5y) were selected.
Global prevalence of malnutrition was 69.9% NRS-2002 (67.3% women/71.7%
men); 83.3% MNA (83.7% women/83%men) and 58.8% VGS (59.2% women/ 58.5%
men). Sarcopenic Obese was detected in 17.5% (12.6% of men; 4.9% of
women). Survival rate was not influenced by gender (p = 0.56), but was influenced by risk of malnutrition (p = 0.017 NRS; p = 0.08 MNA; P = 0.005 VGS) and of sarcopenic obese (p = 0.032).
However, no association was shown between sarcopenic obese and risk of
malnutrition using the Chi-squared tests (p = 0.095 MNA; p = 0.214 NRS; p = 0.429 VSG).
- The risk of malnutrition is statistically associated with a lower survival.
- Sarcopenic obese is statistically associated with a lower survival
- No association has been showed between risk malnutrition and sarcopenic obese in our study
- Further analysis to check if sarcopenic obese modifies risk malnutrition in this setting.
Prognostic usefulness of arm circumference and nutritional screening tools in older patients with cardiovascular disease
Takeshi Nakamura1, Kentaro Kamiya2, Atsuhiko Matsunaga2, Nobuaki Hamazaki1,3, Ryota Matsuzawa3, Kohei Nozaki3, Shinya Tanaka1, Emi Maekawa4, Takashi Masuda2 and Junya Ako4
1Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan; 2Department of Rehabilitation, Kitasato University School of Allied Health Sciences, Sagamihara, Japan; 3Department of Rehabilitation, Kitasato University Hospital, Sagamihara, Japan; 4Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
Several studies have shown that arm circumference (AC) and nutritional
screening tools have prognostic capability in patients with
cardiovascular disease (CVD). However, there have been no direct
comparisons between AC and nutritional screening tools. This study was
performed to compare the prognostic predictive capabilities of AC and
nutritional screening tools in older patients with CVD.
The study population consisted of 1014 admitted patients aged ≥60 years
with CVD. Patients underwent AC measurement and nutritional screening
before hospital discharge. We used the controlling nutritional status
index (CONUT score), the geriatric nutritional risk index (GNRI), and
the prognostic nutritional index (PNI) as nutritional screening tools.
The endpoint of the study was all-cause mortality.
The mean age was 73.0 ± 7.0 years, and 68.0% of the patients were male.
A total of 134 deaths occurred over a median follow-up period of
2.12 years (interquartile range, 2.62 years). After adjusting for
preexisting prognostic factors (including age, gender, body mass index,
estimated glomerular filtration rate, and log B-type natriuretic
peptide), AC (hazard ratio [HR]: 0.57; p < 0.001), CONUT score (HR: 1.24; p = 0.008), GNRI (HR: 0.76; p = 0.031), and PNI (HR: 0.78; p = 0.006)
were significant predictors of mortality. However, adding AC to
preexisting prognostic factors (0.733 vs. 0.705, respectively; p = 0.033), but not CONUT, GNRI, or PNI (0.717, 0.711, and 0.716 vs. 0.705; p = 0.108, p = 0.280, and p = 0.139,
respectively) significantly increased the area under the curve on
receiver operating characteristic analysis.
AC, but not nutritional screening tools, plays a complementary role to
preexisting prognostic factors for predicting prognosis in older patient
Bioelectrical impedance analysis of body composition in obese patients undergoing medical nutrition therapy
Nadja Vasiljevic, Dragana Davidovic, Branko Jakovljevic, Milos Maksimovic and Jagoda Jorga
of Hygiene and Medical Ecology, Faculty of Medicine, University of
Belgrade, Dr Subotica 8, Belgrade, 11000, Republic of Serbia
Background and aim:
Body composition analysis is mandatory in monitoring the effect of
dietary therapy. The aim of this study was to evaluate body composition
variable before and after MNT in obese patients.
The study involved 714 subjects, 173 men and 541 women, who applied to
the Department of Nutrition for MNT for obesity. The body composition
analysis was performed using Tanita BC 418 MA bioelectric impedance for
all patients. Values of fat mass (FM) and fat free mass (FFM) were
obtained, and then the values of FM-Index (FMI) and FFM-index (FFMI)
Results: Body composition analysis showed
that FM and FFM values are higher in subjects with higher BMI. FMI and
FFMI differed significantly among patients within different BMI
categories, as well. These differences are statistically highly
significant in persons of both sexes (p < 0.001). A statistically significant negative correlation (Pearson correlation −0.222; p = 0.003)
was observed in age-related analysis of FFMI in male subjects, while in
female subjects this relationship was not statistically significant (p = 0.059).
After following the hypocaloric diet, there is a decline in FFMI with
increasing age (Pearson correlation −0.273; p = 0.007).
A more detailed analysis shows that the FFMI value is significantly
lower in the group of men older than 55 years (p = 0.005). In the group of women, this relationship is not observed (p = 0.720).
FFMI decrease is in correlation with MNT duration. People who have been
on regime for more than a month have a lower FFMI (p = 0.032).
For the purpose of preserving muscle mass, attention should be paid to
reduction of FFM in all patients who are on restrictive regimens for
long periods of time. Special attention should be given to men older
than 55 years in order to prevent sarcopenia.
Evaluation of an interdisciplinary Cachexia and Nutrition Support Clinic—the patient and carers perspective
Vanessa C. Vaughan1, Meg Harrison2, Anna Dowd2, James Goonan1 and Peter Martin1,2
1School of Medicine, Deakin University, Waurn Ponds, VIC, Australia; 2Barwon Health Cachexia & Nutrition Support Service, Barwon Health, North Geelong, VIC, Australia
The Barwon Health Cachexia & Nutrition Support Service is an
outpatient clinic focused on improving clinical outcomes and quality of
life for patients with or at high risk of cancer cachexia. Patients see
an interdisciplinary team, incorporating a physician, physiotherapist,
dietician and nurse practitioner concurrently. This study aimed to
evaluate the patient and carer perspective of the service.
In 2016/17, semi-structured interviews were conducted with 12 patients
and 9 carers. Interviews focused on two broad themes: 1) recounting
memories and experience of the Cachexia & Nutrition Support Clinic
and 2) describing their ideal experience or expectation of a
cachexia-specific support service. All interviews were recorded and
transcribed verbatim. Thematic analysis was supplemented with data from
reviews of the patient and carer literature.
Analysis generated four superordinate themes that reflected the complex
dynamics of the clinic experience. Themes were improved communication
regarding health literacy/education for patients and carers, empowerment
through person-centred care, evolution of perception of value, and
importance of the interdisciplinary team-based approach. Generally,
patients and carers reported overall positive experiences with the
clinic, particularly with regard to improved communication and
empowerment of the patient.
Conclusions: Findings confirmed
that a cachexia-specific service was viewed as having a positive impact
on quality of life and outcomes by patients and carers. A
patient-centred and individualised approach by the interdisciplinary
team in particular were of importance to those interviewed. These
insights are a critical step in the development of recommendations for
future clinical management of cancer cachexia.
of reduced food intake to cancer-associated weight loss: data from the
International Cancer Cachexia Data Repository
Lisa Martin1, Cathy Kubrak2, Barry Laird3, Bruno Gagnon4, Martin Chasen5 and Vickie Baracos2
1Department of Agricultural, Food & Nutritional Science, University of Alberta, AB, Canada; 2Department of Oncology, University of Alberta, AB, Canada; 3University of Edinburgh, Edinburgh, UK; and European Palliative Care Research Centre; 4Department of Family Medicine and Emergency Medicine, Université Laval, Quebec, Canada; 5Division of Palliative Care, University of Ottawa, Ottawa, Canada
In defining diagnostic criteria for cancer cachexia, a first step was
achieved with the classification of cancer-associated weight loss (WL
Grades) risk stratified for mortality.[1, 2] Next steps relate to the respective roles of reduced food intake and altered metabolism in driving WL.
Here, we tested the prognostic significance of reduced food intake,
using a validated clinical tool designed for patient report.
Methods: Canadian and European patients with cancer formed an international data set (N = 6301). Included patients had recorded overall survival (OS), WL Grade (0 to 4),1 and Patient Generated-Subjective Global Assessment (PGSGA) categories of current food intake.4
Patients relying exclusively on artificial nutrition were excluded.
Data were entered into multivariable Cox proportional hazard
(outcome = OS) and multinomial logistic regression (MLR; outcome = WL
Grade) models, adjusted for age, sex, cancer diagnosis (head and neck,
respiratory, colorectal, gastroesophageal, others) and stage,
performance status, and WL grade.
Results: In the adjusted Cox model, PGSGA food intake categories independently predicted OS (P < 0.001). Compared to “normal food in normal amount” (N = 2190) categories signifying reduced food intake had worse survival:
“normal food in reduced amount” (N = 2804, HR 1.2; 95% CI 1.1–1.3, P < 0.001);
“little solid food” (N = 600, HR 1.6; 95% CI 1.4–1.8, P < 0.001);
“only liquids” (N = 129, HR 1.8; 95% CI 1.5–2, P < 0.001);
“only nutritional supplements (ONS)” (N = 166, HR 1.9; 95% CI 1.6–2.3, P < 0.001);
“very little of anything” (N = 412, HR 1.8; 95% CI 1.6–2.0, P < 0.001).
the adjusted MLR model, patients with reduced food intake were more
likely to have higher WL grades (Grade 1, 2, 3, or 4 vs. Grade 0,
P < 0.001). For example, the probability of Grade 4 WL for patients
with “normal food in normal amount” = 0.09, “normal food in reduced amount” = 0.25, “little solid food” = 0.37, “only ONS” = 0.43, “only liquids” = 0.47, and “very little anything” = 0.43.
Conclusions: Patient-reported food intake categories provide a practical clinical assessment prognostic of OS and higher WL grades.
- 1Diagnostic criteria for the classification of cancer-associated weight loss. J Clin Oncol 2015; 33:90–99., , , et al.
- 2The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysis. J Cachexia Sarcopenia Muscle 2017., , , et al.
- 3Definition and classification of cancer cachexia: an international consensus framework. Lancet Oncol 2011; 12:489–495., , , et al.
H, Ottery FD. Assessing nutritional status in cancer: role of the
Patient-Generated Subjective Global Assessment. Curr Opin Clin Nutr Metab Care 2017.
use of parenteral and enteral nutrition in the oncological setting of a
French University Hospital: adequacy with the recommendations,
efficacy, complications and costs
Lucie Monceau-Baroux1 and Jacques Delarue2
1Brest University Hospital, France; 2Brest University Hospital, France
International evidence-based recommendations regarding the prescription
of parenteral (PN) and enteral nutrition (EN) in cancer patients are
now widely available (ESPEN, ASPEN). However, data from the literature
shows that real-life practice does not always follow those
recommendations, especially in the palliative situation. Financial
toxicity is a new key parameter in medical oncology because more
expensive antineoplastic drugs become available every year and the
French Social Security might not be able to take all the costs in charge
in the future. Nutritional management being part of the supportive care
provided to cancer patients, investigating the costs represented by PN
and EN is mandatory.
Methods: The aim of this study was to
evaluate if the initial prescriptions of artificial nutrition (PN and
EN) made to adult patients with solid tumors in one French University
Hospital during the year 2015 complied with the international
recommendations available at that time. Secondary objectives were to
study the evolution of the nutritional status of the patients under
nutritional support, overall survival from the prescription time, the
rates of septic, metabolic and mechanical complications and the costs.
Between the 01/01/2015 and the 12/31/2015, 111 patients (men: 62%,
women 38%) received parenteral nutrition for the first time and 137
patients (men: 80%, women: 20%) received enteral nutrition for the first
Complete data and analysis will be available in the poster.
The end goal of this study is to have a precise look at the current
practice inside the institution in order to standardize the
prescriptions in the future.
Evaluation of the nutritional status in patients with incurable cancer
Eliana De Rosa, Lidia Santarpia, Maurizio Marra, Maria Carmen Pagano, Lucia Alfonsi, Franco Contaldo and Fabrizio Pasanisi
A.O.U. Federico II, Naples, Italy
Patients with advanced cancer frequently experience malnutrition and
cachexia which, in turn, may negatively influence morbidity, mortality
and quality of life (QoL). The aim of this study was to evaluate the
nutritional status of incurable cancer patients and its correlation with
survival and performance status.
Methods: The nutritional
status of 30 consecutive incurable cancer patients (9 men, 21 women,
aged 60 ± 9 years), eligible for home parenteral nutrition, was
evaluated. The prevalence of cachexia was estimated according to the
grading system developed by Martin et al. in 2015, whilst sarcopenia was evaluated based on Janssen et al.'s 2004 sex-specific cut-points for skeletal muscle (SM) normalized for height.
According to the applied criteria, 100% of patients were cachectic. The
prevalence of moderate and severe sarcopenia was 44.4% in men and 19%
in women, 33.3% in men and 28.6% in women, respectively. Karnofsky score
was ≤50 in 60% and >50 in 40% of patients. Prealbumin serum levels
significantly correlated with survival (R2 = 0.430, p < 0.05).
Mean REE (Resting Energy Expenditure) normalized for fat-free mass
(FFM), (REE/FFM, 30.4 ± 4.5 kcal/kg), was in accordance with age- and
sex-specific values for healthy subjects reported in the literature.
REE, REE/FFM and phase angle were significantly higher in the subgroup
of patients with Karnofsky >50.
dosage and body composition evaluation provide useful information on
patients' prognosis and performance status, in order to identify
incurable cancer patients eligible for nutritional therapy.
Weight history and nutritional status in advanced cancer patients
Eliana De Rosa, Lidia Santarpia, Maurizio Marra, Maria Carmen Pagano, Lucia Alfonsi, Franco Contaldo and Fabrizio Pasanisi
A.O.U. Federico II, Naples, Italy
Overweight and obesity are reported in 40–60% of cancer patients. It's
not clear if obesity provides a survival advantage in patients with
diseases associated with muscle wasting, certainly it could mask the
presence of underlying malnutrition. This study compared the nutritional
status in cancer patients with and without a history of
Methods: We evaluated the nutritional
status of 25 consecutive advanced cancer patients (6 men, 19 women, aged
59 ± 8 years) candidate to home parenteral nutrition. Anthropometric
measures and weight history were collected. Resting energy expenditure
(REE) was measured by indirect calorimetry. Body composition and
skeletal muscle mass (SM) were assessed by bioimpedance analysis.
Janssen et al.'s 2004 sex-specific cut-points for SM normalized for height (SMI) were used to assess the presence of sarcopenia.
Results: Despite mean body mass index (BMI) was 19.6 ± 3.0 kg/m2, and no patients resulted to be obese at the visit, mean habitual BMI was 27.4 ± 7.15 kg/m2,
in particular 32% of patients had a history of obesity and 24% of
overweight. Mean REE and fat-free mass (FFM) were significantly lower (p < 0.05) in patients with habitual BMI <25 kg/m2 (subgroup 1) than in patients with habitual BMI ≥25 kg/m2
(subgroup 2), whilst REE/FFM, SM and SMI showed no significant
differences between the two subgroups. The prevalence of sarcopenia was
72.7% in subgroup 1 and 37.7% in subgroup 2. On the other hand, a
significantly higher (p = 0.001) weight loss, both absolute and
in percentage, was reported by subgroup 2; similarly, main laboratory
markers of malnutrition (serum albumin, transferrin, prealbumin,
pseudocholinesterase) were significantly lower (p < 0.05) in subgroup 2 than in subgroup 1.
This study highlights the importance of weight history in the
nutritional assessment of cancer patients, since it allows to identify
patients with a higher nutritional risk, even when body composition
seems to be preserved.
Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia
Volker Adams1, T. Scott Bowen1, Tina Fischer1, Sarah Werner1, Axel Linke1, Peter Sehr2, Joe Lewis2, Dittmar Labeit3,4, Alexander Gasch3 and Siegfried Labeit3,4
1Department of Internal Medicine and Cardiology, University Leipzig—Heart Center, Leipzig, Germany; 2Chemical Biology Core, EMBL Heidelberg, Germany; 3IPM,
Dept. for Integrative Pathophysiology, Universitätsklinikum Mannheim
University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany; 4Myomedix GmbH, Neckargemünd, Germany
MuRF1 is a muscle-specific ubiquitin E3 ligase that is activated during
clinical conditions associated with skeletal muscle wasting, like
cardiac cachexia, heart failure or cancer. Yet there remains a paucity
of therapeutic interventions that directly inhibit MuRF1 function,
particularly in vivo. The current study, therefore, developed a novel
compound targeting the central B-box-coiled coil domain of MuRF1 in
order to inhibit muscle wasting in cardiac cachexia.
We identified small molecules that interfere with the MuRF1-titin
interaction from a 130,000 compound screen based on Alpha technology. A
subset of 9 prioritized compounds were synthesized by Enamine at 10 g
scale and administrated during conditions of muscle wasting, i.e. to
C2C12 muscle cells treated with dexamethasone and to mice treated with
monocrotaline to induce cardiac cachexia.
Results: The 9 selected compounds inhibited MuRF1-titin complexation with IC50
values <25 μM; of which 3 were found to also inhibit MuRF1 E3 ligase
activity, with 1 further showing low toxicity on cultured myoblasts and
myotubes. This last compound, EMBL chemical core ID#704946, also
prevented atrophy in myotubes induced by dexamethasone and attenuated
fiber atrophy and contractile dysfunction in mice during cardiac
cachexia. Proteomic and Western blot analyses showed that stress
pathways were attenuated by ID#704946 treatment, including
downregulation of MuRF1, and normalization of proteins associated with
apoptosis (BAX) and protein synthesis (elF2B-delta). Furthermore, actin
ubiquitinylation and proteasome activity was attenuated.
We identified a novel compound directed to MuRF1's central myofibrillar
protein recognition domain. This compound attenuated in vivo muscle
wasting, and contractile dysfunction in cardiac cachexia by protecting
de novo protein synthesis and by downregulating apoptosis and
ubiquitin-proteasome-dependent proteolysis. Further studies have to show
if this newly developed compound is also suitable to treat atrophy and
muscle dysfunction in other diseases.
Dantrolene can protect muscle from toxicity induced by chemotherapy using docetaxel
Baptiste Jude1, Thomas Castel1, Florine Tissier1, Karelle Léon1, Mickael Droguet1, Marie-Agnès Giroux-Metges1,2 and Jean-Pierre Pennec1
1EA 4324 ORPHY, IBSAM, UFR Médecine et Sciences de la Santé, Université de Bretagne Occidentale, Brest, France; 2Explorations Fonctionnelles Respiratoires, CHRU de Brest, Brest, France
Many cancers induce cachexia but chemotherapy itself can also induce
cachexia associated to muscle atrophy, inflammation and could be a
limiting factor of cancer treatment. The aim of this study was firstly
to investigate the effects of the docetaxel (Tax), on muscle mass and
inflammation. Secondly, an inhibitor of calcium ryanodine channels, the
dantrolene (Dant), was tested in order to know if it can reduce the
muscular toxicity of docetaxel.
Methods: Three groups were
realized: Sham, Tax (docetaxel at 10 mg/kg), and DanTax (dantrolene at
10 mg/kg 2 h before and 8 h after docetaxel). In a first series, animals
were sacrificed 24 h after treatments for determination of plasma
cytokines and for the activated muscle pathways. In a second series,
animals were sacrificed 7 days after treatments for muscle contraction
recording and atrophy analyses. All values are compared to Sham group.
24 h after treatments, docetaxel-induced muscle atrophy up to 12% for
soleus, 13% for peroneus and 19% for diaphragm whereas in DanTax group
it was mitigated with respectively only 7%, 4.2% and 4.5%. For cytokine
profile, docetaxel led to an increase of INF-γ (+280%), IL-1β (+780%),
IL-6 (+232%) and TNF-α (+400%), but in DanTax group all concentrations
came back to control. 7 days after treatments, there was no significant
atrophy in Tax Group (−4.5% for soleus and −17.5% for diaphragm) but in
DanTax group the muscle mass was increased by +9% for soleus and +7.6%
for diaphragm. For peroneus, atrophy was the same in both groups (−4%).
Maximal force of peroneus contraction decreased in Tax group to 179.2 g
compared to Sham group (215.3 g), and in DanTax group the force was
restored (213.8 g).
Conclusions: The results indicated that
docetaxel induces muscle atrophy associated to the release of
pro-inflammatory cytokines, and that dantrolene can protect muscle from
the deleterious effects induced by docetaxel.
ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass
Rafael Barreto1, Yukiko Kitase2,3, Tsutomu Matsumoto2,3, Matthew Prideaux2,3, Fabrizio Pin2,3, Kyra C. Colston4, Katherine E. Couch4, Marion E. Couch5,6,7, Thomas M. O'Connell3,5,6,7, Lynda F. Bonewald2,3,6 and Andrea Bonetto1,2,3,5,6,7
1Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 2Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA; 3Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA; 4Indianapolis Project STEM, Indiana University School of Medicine, Indianapolis, IN, USA; 5Department of Otolaryngology—Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; 6Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA; 7IUPUI Center for Cachexia Research Innovation and Therapy, Indiana University School of Medicine, Indianapolis, IN, USA
recent progress, chemo- and radiotherapy remain the primary treatment
strategies for cancer, whose development is frequently accompanied by
the occurrence of cachexia, a debilitating condition mainly
characterized by muscle and fat depletion. We recently showed that
chemotherapy, among other toxicities, also contributes to the
development of cachexia by affecting muscle size and strength.
Interestingly, several reports suggest that larger muscle mass
correlates with reduced chemotherapy toxicity and better outcomes. Along
this line, ACVR2B/Fc, an inhibitor of the Activin Receptor 2B
signaling, was shown to preserve muscle mass and prolong survival in
tumor hosts, as well as to increase bone tissue in mouse models of
osteogenesis imperfecta and muscular dystrophy. Hence, we aimed at
investigating the use of ACVR2B/Fc to prevent chemotherapy-associated
toxicities, including muscle and bone depletion.
In order to do
so, we compared the effects of ACVR2B/Fc on body composition, as well as
muscle and bone mass in mice exposed to Folfiri, a combination of
5-fluorouracil, leucovorin and irinotecan, for 5 weeks. Here we show
that ACVR2B/Fc significantly prevented Folfiri-induced loss of muscle
mass and muscle strength. Moreover, it completely counteracted the loss
of trabecular bone in both femurs and vertebrae following Folfiri
administration, as suggested by the analysis of trabecular bone volume
fraction (BV/TV), thickness (Tb.Th), spacing (Tb.Sp), number (Tb.N) and
connectivity density (Conn.Dn). Of interest, Folfiri or ACVR2B/Fc did
not affect the cortical bone in the mouse femur tissue, as shown by
unchanged cortical bone volume fraction (Ct.BV/TV), cortical thickness
(Ct.Th) and porosity.
Overall, our results suggest that ACVR2B/Fc
effectively prevents the loss of muscle and bone mass, as well as muscle
weakness, in animals chronically exposed to chemotherapy. Future
studies will need to validate whether the same protective effects are
observed in combination with different anticancer regimens and/or cancer
A novel Antibody-Oligonucleotide Conjugate (AOC) platform enables efficient regulation of muscle targets in mice
D. Darimont, Rob Burke, Hanhua Huang, Venkata Ramana Doppalapudi,
Rachel Johns, Palani Balu, Michael Cochran, Maria Shahmoradgoli, David
Chu, Gulin Erdogan, Y. Chen, H.W. Kwon, Y. Shi, M. Hood, M. Moon, A.
Cortes, J.D. Arias, Anneke K. Raney and Andrew Geall and Arthur A. Levin
Avidity Biosciences, 10975 North Torrey Pines Road, Suite150, La Jolla, CA, USA
muscular dystrophy and other diseases of muscle are well suited to
treatments using antisense oligonucleotides or siRNAs, efficient
delivery remains the key challenge for oligonucleotide-based therapies
to fulfill their full potential. Targeting oligonucleotides to an
endocytosing liver-specific receptor (ASGPR) through conjugation to its
ligand GalNAc enhanced delivery of oligonucleotides into hepatocytes and
led to various therapies for diseases involving the liver.
we demonstrate that conjugation of oligonucleotide payloads to
antibodies specific for the transferrin receptor (TfR1) facilitates
efficient delivery of siRNAs and single stranded morpholino
oligonucleotides to muscle and other organs. A single IV administration
of 3 mg/kg of a TfR1 mAb-myostatin siRNA conjugate produced significant
(>70%) reductions in levels of myostatin mRNA/protein in vivo. The
knockdown of myostatin lasted for more than 5 weeks and resulted in
increased muscle size and grip strength in wild-type mice. An RISC
loading assay demonstrated that these phenotypic effects were mediated
through an RNAi mechanism. A single dose (5 mg/kg) of a TfR1
mAb-morpholino conjugate enabled exon skipping of exon 23 in dystrophin
pre-mRNA in wild-type mouse skeletal muscle, demonstrating the ability
of antibody oligonucleotide conjugates (AOCs) to support delivery of
diverse oligonucleotide payloads.
The ability to recruit
antibodies and other protein-based scaffolds to deliver oligonucleotides
to specific cell surface receptors for internalization broadens the
number of tissues and diseases that can be targeted with oligonucleotide
therapeutics. The specificity of these therapies can be enhanced
through careful selection of the targeted receptor and/or the
oligonucleotide payload. In addition, delivery of multiple
oligonucleotide payloads and/or the use of therapeutic antibodies
enables potentially greater potency and the regulation of multiple
cellular targets. Studies are ongoing to identify additional receptors
suitable for oligonucleotide delivery and therapeutic oligonucleotides
for the treatment of muscle dystrophies, sarcopenia, cachexia, and other
Mechanisms involved in the cross-talk between humoral and mechanical cues underlying muscle wasting in cachexia
Alexandra Baccam1,2, Medhi Hassani2, Alexandra Benoni1, Martina Ramella3, Francesca Boccafoschi3, Ara Parlakian1, Zhenlin Li1, Zhigang Xue1, Sergio Adamo Sergio2 and Dario Coletti1,2
of Biological Adaptation and Ageing B2A (CNRS UMR 8256 – INSERM ERL
U1164 – UPMC P6), Pierre et Marie Curie University Paris 6, France; 2DAHFMO Unit of Histology and Medical Embryology, and Interuniversity Institute of Myology, Sapienza University of Rome, Italy; 3Dept. Of Health Sciences, University of Eastern Piedmont Avogadro, Novara, Italy
Exercise training improves quality of life and survival of cancer
patients. In an animal model of cancer cachexia we demonstrated that
wheel running counteracts cachexia by releasing the autophagic flux.
Exercise pleitropic effects include the alteration of circulating
factors in favour of an anti-inflammatory environment and the activation
of mechanotransduction pathways in muscle cells. Our goal is to assess
whether mechanostransduciton per se is sufficient to elicit
exercise effects in the presence of pro-cachectic factors of tumor
origin. Serum response factor (SRF) is a transcription factor of pivotal
importance for muscle homeostasis, which is activated with its
co-factor MRTF by mechanostranduction in a way dependent on actin
Methods: We use C26 tumor-bearing mice, in
the absence or presence of wheel running, and mixed cultures of C2C12
myotubes and myoblasts treated with C26 conditioned medium (CM) in the
absence or presence of cyclic stretch to mimic the mechanical
stimulation occurring upon exercise.
Results: In vivo both SRF expression and activity are differentially modulated by the C26 tumor, i.e. by humoral factors, and by exercise. In vitro
we showed that CM had a negative effect on muscle cell cultures, both
in terms of myotube atrophy and of myoblast recruitment and fusion, and
that these effects were counteracted by cyclic stretch. We showed that
CM repressed SRF-MRTF transcriptional activity, while mechanical stretch
rescued their transcriptional activity; in addition, loss of function
experiments demonstrated that SRF was necessary to mediate the
beneficial effects of mechanical stimulation on muscle cells. At least
part of the observed effects were mediated by the balance of pro- and
anti-myogenic factor of the TGFbeta superfamily.
We propose that the positive effects of exercise on cancer patients and
mice may be specifically due to a mechanical response of muscle fibers
affecting the secretion of myokines.
of a novel selective androgen receptor modulator (TEI-SARM2) with once
weekly dosing in rat unloaded muscle atrophy and Duchenne muscular
Masanobu Kanou, Kyohei Horie, Katsuyuki Nakamura, Toshie Jimbo, Hiroyuki Sugiyama and Kei Yamana
Teijin Pharma Ltd, Tokyo, Japan
TEI-SARM2, a non-steroidal selective androgen receptor modulator
(SARM), induces strong anabolism in muscle with minimal effects on
reproductive tissues with once-weekly dosing regimen. In cancer cachexia
models, TEI-SARM2 prevented body weight loss and improved survival
rate. In this study, effects of TEI-SARM2 in animal models of unloaded
muscle atrophy (tail-suspension) and Duchenne muscular dystrophy (DMD)
Methods: Study-1: Female Wistar rats
(12-wk-old) were suspended by the tail to avoid a contact of the
hindlimb with the ground. On day 14, the rats were released from the
suspension to recover for further 14 days. Muscle weight was measured on
days 14, 21 and 28. TEI-SARM2 was administered orally once weekly at
30 mg/kg for 28 days from the day of suspension starting. Study-2: DMD
rats (dystrophin deficient, 5-wk-old) were administered orally
once-weekly at 3–30 mg/kg. Grip force was measured once a month. After
6-month treatment, the rats were monitored for hindlimb force by torque
Results: Study-1: TEI-SARM2 prevented rapid loss
of muscle weight by tail-suspension and accelerated recovery of
gastrocnemius muscle weight to the level of intact animals within
2 weeks after reloading. Study-2: TEI-SARM2 preserved grip force during
6 months in DMD rats. After 6 months, preservation of torque force of
hindlimb was also observed. Surprisingly, anabolic effect was not
confirmed in appendicular muscles, suggesting that there is novel
mechanism of TEI-SARM2 action to improve muscle function other than
Conclusions: TEI-SARM2 prevents muscle atrophy
in atrophic condition and promotes recovery by once-weekly dosing
regimen. In addition, TEI-SARM2 preserves muscle force in DMD rats apart
from muscle hypertrophy. Taken together, TEI-SARM2 could be a promising
drug candidate for various muscle disorders such as disuse muscle
atrophy after hip fracture, DMD and cancer cachexia.
IL-4 counteracts cancer-induced skeletal muscle atrophy: the double-edged sword of IL-4
Domiziana Costamagna1,2, Robin Duelen1, Fabio Penna3, Paola Costelli3 and Maurilio Sampaolesi1,2
Cardiomyology, Stem Cell Biology and Embryology, Department of
Development and Regeneration, University Hospital Gasthuisberg, Leuven,
Belgium; 2Division of Human Anatomy, Dept. of Public Health, Experimental and Forensic Medicine, University of Pavia, Italy; 3Department of Clinical and Biological Sciences, University of Turin, Italy
Background and aims:
Terminal cancer patients frequently present cancer cachexia, a syndrome
causing fat and skeletal muscle weight loss and interfering with
antineoplastic therapies. Interestingly, cancer-induced muscle depletion
seems not only due to hyper-activation of the main proteolytic systems
in muscle tissue but also to an impairment of Satellite Cells (SCs).
Indeed, it has already been reported an increase in the number of
activated myogenic precursors in cachectic muscle, likely unable to
complete the regeneration in vivo (Penna et al., 2010).
to SCs, other cell populations are involved in myogenic
differentiation, such as mesoangioblasts (MABs), vessel-associated
muscle progenitors and Fibro Adipogenic Progenitors (FAPs). Recently, we
demonstrated that BMP-SMAD-signaling blockade improved MAB myogenic
differentiation (Costamagna et al., 2015). Moreover, Fibro
Adipogenic Progenitors (FAPs) have the potential to enhance the
differentiation rate of myogenic progenitors after injury and during
disease progression (Joe et al., 2010; Mozzetta et al., 2013).
this study, we investigated the role of interstitial cells in colon
adenocarcinoma-C26 bearing mice focusing on IL-4 ability to prevent the
detrimental adipocyte differentiation of FAPs in cachectic muscles.
Body weight loss and decreased fiber CSA were partially rescued in
C26-bearing mice daily treated with IL-4 (C26 + IL-4) with respect to
C26 mice. Interestingly, muscle CSA was increased as well in injured
muscles from C26 + IL-4 mice when compared to injured C26, suggesting a
faster regeneration ability. Moreover, IL-4 was able to induce a
decrease in FAPs obtained from C26 + IL-4 muscle explants with respect
to C26 ones.
Conclusions: The results demonstrated that
IL-4 treatment can partially rescue muscle atrophy in tumor bearing mice
undergoing cancer cachexia, probably due to anti-inflammatory
properties. Further experiments are needed to analyze which are the
pathways activated by IL-4 and how this could affect different cell
types present in the muscle.
- 1et al., PLoS ONE, e13604, 2010.
- 2et al., JMCB, 2015.
- 3et al., Nat Cell Biol, 2010.
- 4et al., EMBO Mol Med, 2013.
BIO103 a drug candidate for the treatment of muscle wasting disorders
Maria Serova1, Blaise Didry-Barca1, Sissi On1, Anne-Sophie Foucault1, Sophie Raynal1, Stanislas Veillet1, Pierre Dilda1 and René Lafont2
1Biophytis, UMPC – BC9, 4 place Jussieu, Paris, France; 2Sorbonne Universités, UPMC Univ Paris 06, CNRS - Institut de Biologie Paris Seine (BIOSIPE), Paris, France
Muscle wasting disorders, including cachexia and sarcopenia, are
multifactorial diseases which contribute to overall physical frailty.
They represent a worldwide health challenge with limited therapeutic
options. The aim of this study was to characterize a new small molecule,
BIO103, in vitro on myocytes and in vivo on a mouse model designed to analyse the effects of aging and muscle disuse.
Mouse C2C12 myoblasts were induced to differentiate, and myotube
diameters were measured under fluorescent microscopy. Baseline and
phosphorylated protein levels were assessed by Western blot. Relative
levels of mRNA expression were evaluated using qRT-PCR. Oxygen
consumption was recorded using a Seahorse XF Analyzer. For in vivo studies, 22-month-old C57BL/6J mice were employed. Whole animal physical performances, the in situ functionality of tibialis anterior, and molecular markers of selected muscles were measured after 4 months of treatment.
Using C2C12 cells, BIO103 increased myotube diameter consistently with a
reduction of myostatin and atrogin gene expression. It led to a rapid
activation of AKT/mTOR, MAPK and AMPK signalling pathways and reduced
acetyl-CoA carboxylase activity, suggesting effects on energy
homeostasis and fatty acid synthesis. Moreover, BIO103 was shown to
increase the oxygen consumption rate in muscle cells. In vivo, BIO103
compensated for the significant aging-related loss of running velocity (p < 0.05). These results were associated with increased IGF-1 plasma levels (p < 0.05),
elevated level of p-AMPKα and p-AMPKβ and lower myostatin gene
expression in the gastrocnemius of BIO103-treated animals under high-fat
Conclusions: BIO103, a new orally available small molecule, displays both in vitro and in vivo
anabolic properties, activates AKT/mTOR and AMPK which translates into
improved functional performance, notably in old animals. These
investigations demonstrate the potential of BIO103 in improving skeletal
muscle quality and warrant further studies towards its development as a
drug candidate for the treatment of muscle wasting disorders.
The effects of ERK silencing on muscle cell culture phenotype
Aline R.R. Lima1, Luis H. Zucoloto1, Paula P. Freire2, Mariana J. Gomes1, Luana U. Pagan1, Thierres H.D. Pontes1, Éder A. Rodrigues1, Robson F. Carvalho2, Katashi Okoshi1 and Marina P. Okoshi1
1Botucatu Medical School, Sao Paulo State University – UNESP, Brazil; 2Botucatu Bioscience Institute, Sao Paulo State University – UNESP, Brazil
The mitogen-activated protein kinase family, especially ERK, is
necessary for skeletal muscle mass maintenance. Although rats with
diseases such as heart failure and cancer present muscle atrophy and
reduced ERK expression, the role of ERK in muscle differentiation and
phenotype is poorly understood.
Purpose: To identify
phenotypic effects of a decrease in skeletal muscle ERK protein, ERK
gene was silenced in C2C12 muscle cell culture.
ERK gene silencing was performed by specific RNA interference
(siRNA-ERK). Post muscle differentiation phase, slides were stained with
anti-miosin heavy chain antibody and analyzed by immunofluorescence.
Comparison between groups was performed by Student's t test.
The number of nuclei in multinucleated cells (≥3 nuclei) did not differ
between groups (Control 77.7 ± 22.6; siRNA-ERK 64.7 ± 23.2; p = 0.10). Other data are shown in the table.
ERK has an essential role in myoblast differentiation into myotube and
is important to properly myotube formation and development. These
results corroborate the fact that muscle atrophy is associated with a
reduction in ERK expression.
Effects of late-life enalapril administration on cardiac mitochondria of old rats
Riccardo Calvani1, Vito Pesce2, Giuseppe Sirago2, Anna Picca1, Christy S. Carter3, Guglielmina Chimienti2, Angela Maria Serena Lezza2, Roberto Bernabei1 and Emanuele Marzetti1
of Geriatrics, Neurosciences and Orthopedics, Catholic University of
the Sacred Heart School of Medicine, Teaching Hospital “Agostino
Gemelli”, Rome, Italy; 2Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy; 3Department
of Aging and Geriatric Research, Institute on Aging, Division of
Biology of Aging, University of Florida, Gainesville, FL, USA
Inhibition of the renin-angiotensin system ameliorates age-related
mitochondrial alterations in several rat tissues and increases rodent
lifespan. Here, we investigated the effect of late-life enalapril
administration on mitochondria biogenesis, mitochondrial dynamics,
antioxidant defenses and mitochondrial DNA (mtDNA) content variations in
the heart of old rats.
Methods: Fischer 344 × Brown Norway rats were randomly assigned to receive enalapril (n = 8), or placebo (n = 8)
from 24 to 27 months of age. After sacrifice, the heart was
collected, and total protein and DNA were purified.
Enalapril induced a marked increase in mtDNA content as well as citrate
synthase activity, a marker of mitochondrial mass. Accordingly, a
greater content of mitochondrial biogenesis proteins [i.e., peroxisome
proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and
mitochondrial transcription factor A (TFAM)], mitochondrial fusion
protein mitofusin 2 (Mfn2), mitochondrial antioxidant enzymes superoxide
dismutase 2 (SOD2) and peroxiredoxin III (PrxIII) was found in the same
group. Conversely, the expression of PGC-1β, dynamin-related protein 1
(DRP1) and oxidized PrxIII (Prx-SO3) were unchanged between groups.
Our data indicate that enalapril enhances mitochondrial biogenesis in
the heart of aged rats. As both mtDNA content and mitochondrial
biogenesis are crucial for preserving cellular respiratory capacity, and
PGC-1 is protective against ROS production and oxidative damage, our
results support the hypothesis that the beneficial effects of enalapril
on the heart is mediated at least partly by mitigation of oxidative
stress. The shift of mitochondrial dynamics in rats treated with
enalapril suggests that enalapril administration may promote the
dilution of mitochondrial damage along the network as a further
Synthetic Ghrelin agonists prevents muscle atrophy in an in vitro model of muscle wasting in GHSR-independent manner
Emanuela Agosti2†, Sara Clerici1†, Michele Ferrara1, Elia Angelino1, Nicoletta Filigheddu2, Claudio Pietra3 and Andrea Graziani1,2
1Dept. of Translational Medicine, University of Piemonte Orientale, Novara; 2Dept. of Experimental Oncology, University Vita-Salute San Raffaele, Milano; 3Helsinn Healthcare SA, Lugano, Switzerland
†SC and EA contributed equally.
Acylated and unacylated ghrelin (AG and UnAG, respectively) are
circulating peptide hormones generated in the stomach in response to
fasting and caloric restriction. AG, through binding to its
acylation-selective receptor, GHSR1, induces strong GH release, and
stimulates food intake, adiposity, and positive energy balance. In both
patients and animal models, AG ameliorates cachexia induced by several
pathological conditions through GHSR-dependent mechanisms. However,
recent evidence indicates that both AG and UnAG directly protect
skeletal muscle from experimentally induced atrophy, independently of
GHSR-1a, thus providing the evidence for the existence of an alternative
anti-atrofic ghrelin receptor expressed in the skeletal muscle
(Porporato et al. J. Clin. Invest. 2013). Anamorelin (ANAM),
HM01 are specific GHSR1 agonists, with appetite-enhancing and anabolic
effects. Different clinical studies have highlighted ANAM ability to
improve the cachectic state in cancer patients by increasing total body
mass and food intake, while HM01 was reported to protect mice in a C26
cancer cachexia model.
Methods and Results: In here, we
showed that ANAM and HM01 activate anti-atrophic and hypertrophic
signalling, thus inducing hypertrophy and protecting cultured myotubes
in an in vitro model of IL6-induced muscle wasting. In addition, the
demonstration that ANAM and HM01 induce hypertrophy in myotubes from
GHSR−/− mice provides the genetic evidence that their activity in the
skeletal muscle is independent on GHSR. Finally, HM04, a GHSR
antagonist, impairs the GHSR-independent biological activity of both
ANAM and HM01, as well as that one of AG and UnAG.
Altogether, these observations indicate that i) synthetic Ghrelin
agonists, such as Anamorelin and HM01, are dual agonists acting both
through GHSR, the canonic AG receptor, and the novel, yet unidentified
AG/UnAG receptor, ii) the binding pocket of GHSR and the novel AG/UnAG
receptor share some structural features, albeit GHSR binding requires
Ghrelin acylation; iii) a direct anti-atrophic activity in the skeletal
muscle may contribute to the biological activity of synthetic Ghrelin
agonists in vivo.
Sildenafil modulates catabolic pathways and improves cardiac function in a model of cancer cachexia-induced cardiomyopathy
Vincenzo Musolino1,2,3, Cristina Carresi1,2,3, Micaela Gliozzi1,2, Francesca Bosco1,2, Saverio Nucera1,2,3, Miriam Scicchitano1,2, Delfina Tavano1,2, Ernesto Palma1,2, Carolina Muscoli1,2,3 and Vincenzo Mollace1,2,3
1Institute of Research for Food Safety & Health (IRC-FSH), University of Catanzaro “Magna Graecia”, Catanzaro, Italy; 2NUTRAMED S.c.a.r.l., Roccelletta di Borgia, Catanzaro, Italy; 3IRCCS San Raffaele Pisana, Rome, Italy
Cachexia is a complex metabolic disorder occurring in late stages of
chronic disease including cancer and characterized by involuntary weight
loss caused by an ongoing wasting of skeletal muscle with or without
loss of adipose tissue. Cachexia also affects the cardiac muscle. Heart
atrophy is caused by the hyperactivation of the main cellular catabolic
pathways, including autophagy and Ubiquitin Proteasome System (UPS). As a
consequence of the atrophy of the heart cardiac function is impaired.
Anti-cachectic therapy in patients with cancer cachexia is so far
limited to nutritional support. Sildenafil, a selective inhibitor of the
enzyme phosphodiesterase-5 (PDE5), has been shown to induce myocardial
protective effects, to increase muscle protein synthesis and to reduce
muscle fatigue. We hypothesized that sildenafil ameliorates the wasting
process and the heart function in the Yoshida hepatoma tumor model.
In this study the effects of sildenafil were tested in cachectic
tumour-bearing rats (Yoshida AH-130). Rats were treated daily with
30 mg/kg of sildenafil or vehicle for a period of 16 days. Body weight
and composition were assessed at baseline and at the end of the study.
Cardiac function was analyzed by echocardiography at baseline and at day
Results: Treatment with 30 mg/kg/d of sildenafil
protected the heart from general atrophy. Tumor-bearing rats displayed
cardiac dysfunction, as indicated by the significant impairment of the
left ventricular ejection fraction and the left ventricular fractional
shortening. In contrast, sildenafil improved cardiac dysfunction.
Western blotting analysis showed an upregulation of the autophagy and of
the UPS in the hearts of the vehicle-treated tumour-bearing rats.
Treatment with Sildenafil, however, was able to modulate the UPS markers
(e.g. TRAF6 and Atrogin-1) in the hearts of tumour-bearing rats.
Moreover, cachexia led to an up-regulation of eNOS and iNOS in the
hearts of tumor-bearing rats. Sildenafil was able to down-regulate the
expression of the enzymes. Although sildenafil did not reduce the loss
of lean body mass, it showed a trend to protect from adipose tissue
Conclusions: Sildenafil treatment in the Yoshida
hepatoma model showed an attenuation of fat tissue loss in animals with
progressive weight loss in cancer cachexia. Moreover, the drug protects
the heart from atrophy through a down regulation of the catabolic
markers and presumably through a modulation of the NOS/NO pathway. This
effect led to a significant improvement of cardiac function. While
mounting evidence supports the implication of the NOS/NO pathway in
muscle wasting, many questions remain unanswered. Larger studies with
longer follow-up and molecular analysis are required to verify whether
sildenafil could ameliorate cardiac wasting and function by modulating
inflammation and catabolic pathways.
Musclin: an exercise-induced myokine useful to contrast muscle wasting during cancer
Andrea David Re Cecconi, Giulia Benedetta Martinelli, Sara Previdi, Sergio Marchini, Luca Beltrame and Rosanna Piccirillo
Oncology Department, IRCCS-Mario Negri Research Institute for Pharmacological Research, Milan, Italy
Physical activity extends life span of patients affected by certain
types of cancer, also by contrasting the associated muscle wasting (i.e.
cachexia). The most effective type of physical activity against muscle
wasting during cancer seems to be aerobic exercise. So we asked whether
it promotes secretion of proteins by muscles (i.e. myokines) that may
contrast cancer cachexia.
Methods: To mimic aerobic
exercise, we infected C2C12 myotubes with PGC1α-expressing adenoviruses,
because PGC1α is the main transcriptional coactivator involved in
muscle adaptation during aerobic exercise.
microarray analysis showed musclin as a PGC1α-induced myokine. We
further immunoprecipitated it only from supernatants of PGC1α expressing
myotubes. By Q-PCR, we found musclin expression unchanged in myotubes
hypertrophying because of activated AKT (to mimic anaerobic exercise).
Among other PGC1α-induced myokines, we found only musclin strongly
downregulated in cachectic muscles and plasma of C26-bearing mice even
at times when their body weights were not lost yet. Thus, we
electroporated Tibialis Anterior (TA) of C26-bearing mice with
musclin-encoding plasmids and found musclin to preserve fiber area.
myotubes or FoxO3-expressing myotubes undergo atrophy as measured by
increased rates of proteolysis and MuRF1 induction. Unlike GFP, musclin
was able to contrast the dexamethazone induced-MuRF1 expression in
Luciferase assays. Notably, musclin-containing supernatants of PGC1α
expressing myotubes restrained the FoxO3-induced rates of long-lived
Conclusions: Musclin is a myokine
induced specifically by PGC1α, typically increased upon aerobic exercise
and musclin overexpression is beneficial against muscle wasting during
C26 growth or in atrophying myotubes. Overall, musclin would be a good
drug option for cancer patients that cannot exercise and are at risk of
Skeletal muscle myotubes show decreased protein synthesis and viability after treatment with chemotherapy
Francina J. Dijk1, Bram Dorresteijn1, Yvette Luiking1,2, Onno Kranenburg3, Marion Jourdan1 and Miriam van Dijk1
1Nutricia Research, Nutricia Advanced Medicial Nutrition, Utrecht, the Netherlands; 2Center for Translational Research in Aging and Longevity, Department of Health and Kinesiology, Texas A&M University, USA; 3Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, the Netherlands
Chemotherapy is a very non-specific treatment that targets all highly
proliferating cells like cancer cells, but also healthy cells including
skeletal muscle cells. Cancer itself can cause muscle wasting
(cachexia); however, limited information is available on the direct
effect of chemotherapy on skeletal muscle. A combination of capecitabine
(a pro-drug of 5-fluorouracil) and oxaliplatin is often used as a
chemotherapy treatment for colorectal cancer patients. This study aimed
at investigating the effects of 5-fluorouracil and oxaliplatin, either
alone or combined, on protein synthesis (MPS), cell-viability and
apoptosis/necrosis in a model for skeletal muscle (C2C12-myotubes).
Methods: C2C12-myotubes were incubated for 24 h with a concentration range of oxaliplatin (OX; 2–125 μM, n = 3), 5-fluorouracil (5FU; 2–250 μM, n = 2), oxaliplatin and 5-fluorouracil combined 1:1 (OXF; 2–250 μM, n = 3)
or left untreated (control). Subsequently, after a 4 h serum- and
leucine-free period, MPS was measured by puromycin incorporation by the
SUnSET method. In parallel, cell viability was measured by
CellTiter-Glo, apoptosis by Caspase-Glo and necrosis by LDH-release
directly after chemotherapy incubation. Statistical analyses by ANOVA
with post-hoc LSD versus control.
Results: MPS was inhibited dose-dependently by both OXF and OX from 15.6 μM (P < 0.0056). In contrast, 5FU only inhibited MPS at the highest dose of 250 μM (P < 0.0056).
OXF decreased cell viability significantly from 31.3 μM, whereas OX
decreased cell viability significantly from 15.6 μM. Both OX and OXF
increased apoptosis and necrosis from 15.6 μM to 31.3 μM, respectively (P < 0.0056). 5FU decreased cell viability from 62.5 μM (P < 0.0056) and apoptosis only at 250 μM (P < 0.0056) while necrosis was unchanged.
Myotubes are compromised by chemotherapy treatment, with a decrease in
protein synthesis and cell viability and increases in apoptosis and
necrosis. The impact is chemotherapy and dose dependent. While the
compromised effect of 5-fluorouracil is evident at levels exceeding
pharmacological doses, oxaliplatin is more toxic to myotubes than
5-fluorouracil, even in low doses and given either alone or combined.
of formoterol on atrophy signaling, autophagy, and muscle phenotype in
respiratory and limb muscles of rats with cancer-induced cachexia
Anna Salazar-Degracia1, Sílvia Busquets2,3, Josep M. Argilés2,3, Esther Barreiro1 and Francisco J. López-Soriano2,3
Department-Muscle Wasting and Cachexia in Chronic Respiratory Diseases
and Lung Cancer Research Group, IMIM-Hospital del Mar, Parc de Salut
Mar, Health and Experimental Sciences Department (CEXS), Universitat
Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB),
Barcelona, Spain; 2Cancer Research Group,
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia,
Universitat de Barcelona, Barcelona, Spain; 3Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
Introduction and purpose:
Muscle mass loss and wasting are characteristic features of patients
with chronic conditions including cancer. Beta-adrenergic receptor
agonists attenuate muscle wasting. We hypothesize that muscle atrophy
signaling pathways and altered metabolism may be attenuated in cancer
cachectic animals receiving a treatment with formoterol.
Rats bearing the Yoshida AH-130 ascites hepatoma (7 days) were treated
daily with formoterol (0.3 mg/kg body weight, subcutaneously).
In diaphragm and gastrocnemius of cancer cachectic rats, fiber sizes
were reduced, levels of structural alterations, atrophy signaling
pathways, proteasome content, protein ubiquitination, autophagy, and
myostatin were increased, while those of regenerative and metabolic
markers (myoD, mTOR, and PGC-1alpha) were decreased.
Treatment with formoterol attenuates the structural alterations and
atrophy signaling, while improving other molecular perturbations. These
results have relevant therapeutic implications, showing beneficial
effects of formoterol in cachectic muscles through several key
Fenofibrate prevents skeletal muscle loss in lung cancer-induced cachexia
Marcus D. Goncalves1, Seo-Kyoung Hwang1, Chantal Pauli2, Charles J. Murphy1, Zhe Cheng1, Guoan Zhang1 and Lewis C. Cantley1
1Weill Cornell Medical Center, New York City, USA; 2Institute for Pathology and Molecular Pathology
Cancer cachexia is a systemic metabolic disorder with high mortality
characterized by catabolism of nutrient rich tissues with no effective
treatment. This condition is particularly prevalent in non-small cell
lung cancer (NSCLC), where loss of skeletal muscle results in functional
impairment and increased mortality. The aim of the current study was to
assess the changes in systemic metabolism in a genetically engineered
mouse model of NSCLC in an attempt to identify novel therapeutic
Methods: NSCLC was induced in adult KrasG12D/+Lkb1flx/flx
(KL) mice with intranasal adenovirus containing Cre recombinase and the
mice were followed for changes in body weight and food intake. Cachexia
was a priori defined as a 10% loss in body weight from the peak weight
obtained during the study. Serum and tissue metabolites, hormones, and
cytokines involved in nutrient homeostasis in tumor-bearing mice were
measured and compared to fed and fasted mice using mass spectrometry and
commercially available assays. RNA sequencing of the liver and skeletal
muscle was performed to identify differential variables with adjusted
p-values below 0.05 and log-transformed fold-change greater than 1
between the subgroups of mRNA expression using DESeq2 (v1.14.1).
Sixty percent of KL mice develop loss of skeletal muscle, loss of
adipose tissue, and increased inflammatory markers mirroring the human
cachexia syndrome. Using non-cachexic and fasted animals as controls, we
report a unique cachexia metabolite phenotype that includes the loss of
PPARα-dependent ketone production by the liver. In this setting,
glucocorticoid levels are increased and correlate with reduced type 2
myofiber size and increased markers of hepatic gluconeogenesis.
Restoring ketone production using the PPARα agonist, fenofibrate,
reversed the metabolic changes in hepatic metabolism and prevented the
loss of body weight and skeletal muscle.
study characterized a new model of lung cancer induced cachexia and
provides evidence for a novel therapeutic strategy for cachexia focused
on hepatic ketone production using the well-tolerated, generically
available drug, fenofibrate.
BGP-15 co-therapy protects against chemotherapy-induced cachexia
Dean G. Campelj1,2, Cara A. Timpani1,2, James C. Sorensen1,2, Craig A. Goodman1,2,3, Alan Hayes1,2,3 and Emma Rybalka1,2,3
1College of Health & Biomedicine, Victoria University, Melbourne, Australia; 2Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, Australia; 3Institute of Sport, Exercise & Active Living (ISEAL), Victoria University, Melbourne, Australia
Introduction: Chemotherapy-induced muscle wasting and dysfunction has emerged as a contributing factor to cancer cachexia[1, 2] and increases the risk of morbidity and mortality.
Thus, developing strategies to protect and preserve skeletal muscle
during anti-cancer therapy is paramount. Here, we investigate the
effects of irinotecan (IRI), a topoisomerase-1 inhibitor used in the
treatment of colorectal cancer, on skeletal muscle mass and function.
Further, we have evaluated the pharmacological small molecule, BGP-15, a
poly-ADP ribose polymerase-inhibitor, to ameliorate IRI-induced
skeletal muscle pathology.
Methods: 6-week old male Balb/C
mice were treated with 6 intraperitoneal injections of either vehicle
(0.1% DMSO), IRI (30 mg/kg) or IRI + BGP-15 adjunct therapy (15 mg/kg)
over two weeks. Through in vivo and ex vivo
experiments, body composition, whole body metabolic and voluntary
activity levels, contractile properties and mitochondrial function were
Results: IRI reduced lean mass (p < 0.05) and the absolute force production of the soleus (SOL; p < 0.0005) and extensor digitorum longus (EDL; p < 0.05) muscles. Remarkably, BGP-15 co-therapy was protective, attenuating the IRI-induced loss of lean mass (p < 0.005) and absolute force production of both the SOL (p < 0.0005) and EDL (p < 0.05). In flexor digitorum brevis fibres, IRI (both alone and in combination with BGP-15) increased the oxidative metabolic potential (p < 0.05), a marker of mitochondrial functional capacity, which was achieved by improving coupling efficiency (p < 0.05). BGP-15 co-therapy also improved the glycolytic metabolic potential (p < 0.05), a marker of anaerobic capacity. These metabolic data are consistent with a reduced whole body VO2 (ml·min−1·g−1) at rest (p < 0.05) in IRI-treated mice and suggest induction of an “energy conservation” phenotype in the skeletal muscle.
Our study is the first to show that IRI treatment induces skeletal
muscle dysfunction and wasting, which was attenuated with BGP-15
co-therapy. These findings highlight the potential of BGP-15 to improve
patient quality of life during and following anti-cancer chemotherapy.
- 1Cancer Chemo Pharmacol 2016; 78(4):673–83. et al.,
- 2 Gilliam & St. Clair, Antiox Redox Sig 2011; 15(9):2543–63.
- 3J Cachex, Sarco Mus 2013; 4(2):89–94. et al.,
supplementation prevents skeletal muscle atrophy by attenuating
systemic pro-inflammatory condition and protein degradation in
Rafael Deminice1, Paola S. Cella1, Mayra J. Testa1, Fernando H. Borges2, Poliana C. Marinello1,2, Patricia C. Perandini1, Rubens Cechinni2, José A. Duarte3 and Flávia A. Guarnier2
1Department of Physical Education, State University of Londrina, Brazil; 2Department of Pathology, State University of Londrina, Brazil; 3CIAFEL, Faculty of Sport, University of Porto, Porto, Portugal
To investigate the effects of creatine supplementation on skeletal
muscle protein degradation signaling in Walker-256 tumor-bearing rats.
Methods: Thirty-two male Wistar rats were assigned to four (n = 8)
groups: control (C), creatine supplemented (Cr), tumor-bearing (T) and
tumor-bearing creatine supplemented (TCr) rats. Creatine monohydrate was
supplied in drinking water in a total of 21 days (8 g/L). Tumor
implantation was performed on the eleventh day of creatine
supplementation; rats were euthanized ten days after tumor cells
inoculation. Tumor cells inoculation consisted of a suspension of
Walker-256 cells (7.0 × 107cells).
Results: The progressive increase in tumor mass (9% of body weight at 10th day) coincided with lower (P < 0.05)
body mass (−11%) and muscle wasting (−31% soleus CSA) in T compared to C
group. In addition, tumor growth promoted elevated (P < 0.05) systemic leukocytes (1.2-fold, P < 0.05), increased circulating inflammatory interleukins (TNF-α 2.6-fold and IL-6 4.4-fold increase, P < 0.05)
and muscle oxidative stress demonstrated by increased MDA (54%) and
decreased GSH/GSSG (−61%) ratio in T compared to C group. Tumor growth
also promoted increased protein expression of MuRF1 and Atrogin1. In
contrast, creatine supplementation mitigates body weight loss and muscle
wasting (6% and 24% of attenuation in TCr group compared to T,
respectively, P < 0.05). Tumor-induced systemic
pro-inflammatory condition, muscle oxidative stress and elevated
ubiquitin ligases were also attenuated by creatine supplementation.
Therefore, decreased expression of MuRF1 and Atrogin1 mediated by the
attenuation of pro-inflammatory condition is thought to be responsible
for the preventive effects of creatine supplementation on muscle loss.
Mean life span was not different between groups (TCr 26.4 ± 2.2 vs T
22.0 ± 2.7, days).
Conclusions: Creatine supplementation
prevents cachexia development and muscle wasting by attenuating
tumor-induced systemic pro-inflammatory condition and muscle oxidative
stress; condition that may down-regulates important regulators of
ubiquitin mediated protein degradation Atrogin-1 and MuRF-1 in skeletal
Supported by Capes-PVE # 88881.068035/2014-01
Targeting mitochondria with SS-31 in experimental cancer and chemotherapy-induced cachexia
Riccardo Ballarò1,2, Marc Beltrà1,2, Paola Costelli1,2, Hazel Szeto3 and Fabio Penna1,2
1Department of Clinical and Biological Sciences, Experimental Medicine and Clinical Pathology Unit, University of Turin, Italy; 2Interuniversity Institute of Myology, Italy; 3Mitochondrial Therapeutics Consulting, New York, NY, USA
cachexia is a debilitating muscle wasting condition defined also as an
energy-wasting syndrome (1). Mitochondria play a central role, being the
main energy source. Indeed, mitochondrial alterations and low
intracellular ATP have been found in the skeletal muscle of cachectic
The present study aimed at evaluating the effects of a
mitochondrial-targeted compound (SS-31) on muscle wasting in
C26-bearing mice either under unrestricted tumor growth (C26; 14 days of
tumor growth) or treated with chemotherapy
(oxaliplatin + 5-fluorouracil; C26 OXFU; 28 days of tumor growth).
with unrestricted tumor growth exhibited a reduction of muscle mass,
muscle strength and food intake. OXFU administration was able to double
the lifespan of C26 mice, although resulted in exacerbated muscle
wasting. SS-31 administration counteracted body weight and food intake
loss in C26 mice and, while borderline significantly protected from
muscle wasting. Regarding mitochondrial markers, both C26 and C26 OXFU
animals exhibited a reduction of PGC-1α, Cytochrome c and SDH protein
levels with no effect of SS-31 administration. In C26 OXFU mice, also
the SDH total activity and ATP content were reduced. In C26 mice SS-31
increased SDH activity and ATP content. Mitochondrial alterations found
in C26 mice also associated with a strong reduction in protein synthesis
that was improved by SS-31 treatment.
In conclusion, targeting
mitochondria with SS-31 exerts some beneficial effects on C26-bearing
mice with unrestricted tumor growth, partially protecting from body
weight and food intake loss, muscle wasting and counteracting the
impairment of muscle oxidative capacity leading to energy wasting.
Further investigation and treatment optimization is required in order to
demonstrate a potential effectiveness of SS-31 in the more severe
chronic model (C26 OXFU mice).
JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia:
understanding the molecular basis. Nat Rev Cancer. Nature Publishing
- Pin F, Busquets S, Toledo M, Camperi A, Lopez-Soriano FJ, Costelli P, et al.
Combination of exercise training and erythropoietin prevents
cancer-induced muscle alterations. Oncotarget. 2015;6(41):43202–15.
double-blind placebo controlled clinical trial into the physiological
impacts of testosterone administration during resistance exercise
training in older men
Nima Gharahdaghi, Supreeth Rudrappa,
Bethan Phillips, Iskandar Idris, Mathew Brook, Daniel J. Wilkinson, Nate
Szewczyk, Kenneth Smith and Philip Atherton
MRC-ARUK Centre of Excellence and NIHR BRC, School of Medicine, University of Nottingham, UK
The andropause is associated with declines in serum testosterone and an
associated loss of skeletal muscle mass and function (i.e. sarcopenia),
and insulin resistance. Two of the major interventions purported to
offset sarcopenia are testosterone (T) therapy and resistance exercise
training (RET); however, the benefits of T coupled to RET are poorly
defined—especially on the back drop of ‘anabolic resistance’ of ageing.
The purpose of this study was to determine the effect of RET plus T (vs.
placebo) in relation to body composition, muscle mass, strength and
oral glucose tolerance.
Methods: Sixteen non-hypogonadic healthy older men, 65-75 y, BMI ≤30 kg·m−2 (serum total T > 8.3 nmol·l−1) were randomly assigned in a double-blinded fashion to receive bi-weekly: either placebo (P, n = 8) or testosterone (T; Sustanon 250-mg, n = 8)
injections over 6-week whole-body RET. RET consisted of leg extension,
leg press, leg curl, lat pull down, shoulder press and bench press (3
sets, 8–10 reps at 80% 1-RM). Dual energy x-ray absorptiometry (DXA),
muscle ultrasound, isokinetic dynamometry and oral glucose tolerance
tests (OGTT) were used to quantify body composition, muscle
architecture, maximal voluntary contraction (MVC) and glycaemic control,
Results: T adjuvant to RET, augmented total lean mass (5.29 ± 2.67% vs 1.18 ± 2.84%, P = 0.01,
ES = 0.79), appendicular lean mass
(24520 ± 2739 g to 26133 ± 3075 g vs.
24978 ± 3813 g to 25166 ± 3438 g, P = 0.023, ES = 0.42), m.vastus lateralis thickness (VL) (P < 0.0001, ES = 0.38), 1-RM leg extension (P < 0.0002, ES = 0.61) and leg curl (P = 0.005, ES = 0.39). However, no group differences (P > 0.05)
were observed in MVC or fascicle length/pennation angle. Additionally,
T decreased body fat 6.40 ± 3.66% (P = 0.017, ES = 0.25) vs. P. There was no significant impact of T/RET in relation to OGTT (P > 0.05).
T therapy, adjuvant to RET, enhanced muscle mass (i.e. thus
“overcoming” anabolic resistance), whilst simultaneously decreasing body
fat without impacting glycaemic control. T therapy coupled to RET is an
effective short-term intervention to improve muscle mass/function in
SARA Clinical program for evaluating safety and efficacy of Sarconeos in a Phase 2b clinical trial
Waly Dioh1, Carole Margalef1, Philippe Dupont1, Pierre Dilda1, René Lafont2, Stanislas Veillet1 and Susanna Del Signore1
1Biophytis, UMPC – BC9, 4 place Jussieu75005, Paris, France; 2Sorbonne Universités, UPMC Univ Paris 06, CNRS - Institut de Biologie Paris Seine (BIOSIPE), 75005, Paris, France
Sarcopenia is a key underlying cause of physical frailty, a reversible
condition in older subjects, which may lead to mobility disability and
dependency. Sarcopenia is characterized by the loss of muscle mass and
function. Biophytis has developed the drug candidate Sarconeos (BIO101)
acting via Mas, the Angiotensin1–7 receptor for prevention and treatment
of Sarcopenia. Mas receptor is one of the components of the
Methods: Specifically, the SARA
clinical program was developed with Sarconeos (BIO101) in age-related
sarcopenia and is composed of three main studies:
completed SARA-PK Phase 1 study that evaluated Sarconeos safety profile
in young and elderly volunteers up to 1400 mg/day in single
administration and up to 900 mg/day after 14-day multiple oral
- The ongoing
SARA-OBS observational study that aims to validate applicability of
inclusion criteria based on sarcopenia definition according to the
Foundation of NIH (Studenski et al., 2014) and a very low Short Physical Performance Battery (SPPB; Guralnik J et al.,
1994). This study will also evaluate functional (6 minutes walking
distance: 6MWD and 400 meters test) and three Patient Reported Outcomes
(SF-36; SarQoL, TSD-OC) parameters.
SARA-INT interventional phase 2 study that will evaluate safety and
efficacy of two oral doses of Sarconeos versus placebo in older
sarcopenic patients (scheduled for second semester 2017).
All data are hosted within the SARA dedicated platform, allowing real-time monitoring.
Our presentation will focus on 1) Sarconeos effects on a battery of
pharmacodynamic plasma biomarkers (Myoglobin, PIIINP etc.) as observed
in SARA-PK. 2) Preliminary baseline data of SARA-OBS on target
population and primary (6 MWD/400 meters and Patient Reported Outcomes)
and secondary endpoints. And, 3) SARA-INT methodology for investigating
Sarconeos safety and efficacy in sarcopenic older patients.
Conclusions: The SARA clinical program will allow to outline the effects of Sarconeos on age-related sarcopenia.
electrical stimulation (NMES) during hemodialysis improves muscle mass
and function in chronic renal disease patients
Ana C. Marini1, Reika D. Motobu1, Bruna M. Giglio1, Renata C. Fernandes1, João F. Mota1, Fabio S. Lira2, Ana T.V.S. Freitas1, Alessandro Laviano3, Benjamin T. Wall4 and Gustavo D. Pimentel1
and Sports Nutrition Research Laboratory (Labince), Nutrition Faculty
(FANUT) – Federal University of Goias (UFG), Goiânia, GO, Brazil; 2Immunometabolism
Research Group, Department of Physical Education, São Paulo State
University (UNESP), Presidente Prudente, SP, Brazil; 3Department of Clinical Medicine, Sapienza University, Rome, Italy; 4Department of Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK
Background and aims:
Renal failure patients undergoing hemodialysis experience significant
loss of muscle mass and function, which in turn contributes to poor
clinical outcome. Physical inactivity contributes to loss of muscle mass
and function. NMES elicits muscle contraction and has been shown to
attenuate muscle atrophy when physical activity is not feasible or
tolerated. Therefore, we hypothesized that regular NMES during dialysis
sessions may improve muscle mass and function.
Adult renal failure patients, receiving hemodialysis 3 times/week, were
considered for the study. Patients were randomly assigned to usual care
(control group) or to NMES. NMES was applied bilaterally to both thighs
and calves, at the origin and insertion points of muscle for 40 min
during each hemodialysis session for 1 month. Skeletal muscle mass index
(SMI; g/m2), muscle function and performance were assessed
at the beginning and at the end of the study period by anthropometry,
BIA, handgrip strength (Kg) and gait speed (m/sec). Results were
statistically analyzed by Student's t-test, and data are reported as
M ± SD.
Results: Twenty-one patients were studied (x = 8 women, x = 13 male; 45.8 ± 10.6 yr). In NMES-treated patients (n = 10;
6 M/4F), SMI increased significantly at the end of the study when
compared to control group (+0.35 kg/m2 vs. −0.41 kg/m2, respectively; p = 0.007). Gait speed improved in NMES-treated patients at the end of the study (+0.07 m/s; p = 0.04), whereas it remained unaltered in the control group (−0.02 m/s; p = 0.70).
At the end of the study period, no significant change in handgrip
strength was observed in NMES and control groups (p = 0.28 and p = 0.08, respectively).
Thirty days of NMES targeting muscles of the legs may improve muscle
mass and function in patients with chronic renal failure and undergoing
in muscle quality following 12 weeks of power training in
mobility-limited older adults: a randomized controlled trial
Jonathan Vaarst1, Mikkel Kolind1, Lars N. Hvid2, Marianne Andersen3 and Paolo Caserotti1
of Sports Science and Clinical Biomechanics, SDU Muscle Research
Cluster (SMRC), University of Southern Denmark, Odense, Denmark; 2Section for Sport Science, Department of Public Health, Aarhus University, Aarhus C, Denmark; 3Department of Endocrinology, Odense University Hospital, Odense, Denmark
Aging is associated with a loss of muscle strength that exceeds the
loss of muscle mass, which ultimately translates into reduced muscle
quality (MQ: strength per unit of muscle mass). The decline in muscle
strength is greater in mobility-limited older adults compared to
well-functioning older adults, and MQ may be even poorer in this group.
There is evidence that power training counteracts the loss of function,
although it is unclear to which extent this exercise regime affects
muscle mass, strength and quality, especially in mobility-limited older
adults. This study investigated the effect of 12 weeks of progressive
high-intensity (70–80% of 1 RM) power training on muscle quality in
mobility-limited participants aged 75+.
older adults with usual gait speed <0.9 m/s (age:
82.4 ± 4.8(mean ± SD), 66.2% female) were randomized to a control group
(CG) or training group (TG). Fifty-one participants had complete cases
(CG: n = 27, age 82.8 ± 5.2, 77.8% women); (TG: n = 24,
age 82.6 ± 4.5, 50% women). Muscle strength was assessed as an
isometric single-leg maximum voluntary contraction (MVC) normalized to
body weight (N/kg). Leg muscle mass (LMM) of the dominant leg was
determined using dual-energy X-ray absorption (DXA – Hologic Inc,
Bedford, MA). MQ was calculated as MVC divided by LMM.
Results: Muscle strength increased by 2.6 ± 2.9 N/kg (27.2%) in the TG with no changes in the CG (TG vs CG; p < 0.01). LMM did not change in either group. MQ increased by 28.6 ± 32.0 N/kgLMM (27.9%) in the TG with no changes in the CG (TG vs. CG; p < 0.01).
The results indicate that progressive power training is effective in
improving MQ in mobility-limited older adults and that these changes
primarily are mediated by increases in muscle strength with no changes
in muscle mass.
Physical mobility and survival in older Chileans
Cecilia Albala1, Lydia Lera1, Barbara Angel1, Carlos Marquez1, Rodrigo Saguez1, Florencia Danioni3, Patricia Arroyo2 and Felipe Salech2
1INTA, Universidad de Chile, Santiago, 7640765, Chile; 2Clinical Hospital Faculty of Medicine, Universidad de Chile, Chile; 3Medical student Faculty of Medicine, Universidad de Chile, Chile
Background: Physical Mobility is a key issue for maintaining independence in older people.
To study the association of self-reported physical mobility, defined as
ability to walk eight blocks and leisure time physical activity (LTPA)
practice, with survival in older Chileans.
up of the Alexandros cohorts designed to study disability associated
with obesity in community-dwelling people 60 y and older living in
Santiago/Chile. At baseline 2395 participants, mean age 69.6 ± 7.1 y
(min 60; max 100), 67.1% women, underwent home interviews including
history of chronic diseases, self-reported disability/functional
limitations, ability to walk 8 blocks and LTPA were performed.
Anthropometry, dynamometry and physical performance were measured.
Information about deaths was available for the whole sample. Cox
proportional hazard models and Survival probabilities according ability
to walk eight blocks and LTPA at baseline were built.
At baseline 62% of the participants reported no limitations in walking
eight blocks, 30.3% some limitations and 7.7% inability. Only 10.8%
reported LTPA at least 3 times per week with 74.2% of the sample never
practicing. After 10–14 years of follow up and 24459 person/years at
risk 469 people were died. After adjusting by age, sex, BMI, smoking and
education, the hazard ratios for death associated with limitation for
walking 8 blocks was HR = 1.84 (95%CI:1.49–2.28) and the protective
effect of practicing physical activity ≥3 times/week was HR = 0.04
The probability of survival at 12–14 y
according ability to walk eight blocks was 0.84 (95%CI 0.82–0.86) for
people with no limitations and 0.62(95%CI 0.58–0.66) for people with
For people practicing LTPA ≥3 times/week
the probability of survival at 12–14 y was 0.988 (0.9633–0.9961) vs.
0.748 (0.6987–0.7907) for people practicing LTPA 1–2 times/week or
Conclusions: Ability to walk 8 blocks and physical
activity ≥3 times per week are independently associated with higher
survival in older Chileans.
Funding: Fondecyt Grants 1080589 & 1130947
Concurrent training does not impair myonuclei addition in elderly
Miguel Conceição1,3, Claudia Cavaglieri1, Cleiton Libardi2, Felipe Vechin3, Mara Patricia Chacon-Mikahil1, Aline Bacurau3, Patricia Chakur Brum3 and Carlos Ugrinowitsch3
1University of Campinas, SP, Brazil; 2Federal University of São Carlos, SP, Brazil; 3University of São Paulo, SP, Brazil
It is well known that aging is associated with sarcopenia and
cardiovascular problems. To reduce the burden, elderly should perform
both resistance training (RT) and endurance training (ET), called
concurrent training (CT). However, CT can hamper muscle strength and
hypertrophy gains compared to RT alone, phenomenon known as interference
effect. Interestingly, the physiological mechanisms behind interference
effect are uncertain. Recently, it was showed the importance of
satellite cells (SC) to muscle hypertrophy. After activation, SC enter
the cell cycle, proliferate and may fuse and donate their nuclei to
existing muscle fibres. The donation of myonuclei is nedeed when
increased transcription capacity is required, such as to promote protein
accretion. Nevertheless, no study has investigated changes in myonuclei
number after CT, in elderly.
Objective: To compare myonuclei number after 12 weeks of CT and RT in elderly.
24 healthy subjects (64 ± 4 years, 64 ± 4 kg, 1.64 ± 0.11 m) were
randomly allocated in one of the following groups: concurrent training
(CT, n = 8), resistance training (RT, n = 9) or control group (GC, n = 7).
A muscle biopsy was undertaken before and 48 after the last training
session. Maximum strength test (1-RM), maximal oxygen uptake (VO2max)
test and magnetic resonance imaging (MRI) were also assessed pre- and
post-training. RT was performed twice a week in the leg press 45°
(4 × 10 at 70–80% of 1-RM). CT performed the same RT protocol followed
by walking/running at 60–85% of VO2max during 40–50 min.
CT and RT significantly increased muscle strength and hypertrophy after
intervention with no difference between them. There were no changes in
myonuclei number in all groups.
Conclusions: 12 weeks of CT
increase muscle strength and hypertrophy similarly to RT. Also, neither
CT nor RT showed myonuclei addition suggesting that pre-existing
myonuclei induced muscle growth.
physical activity at moderate and high intensity is associated with
parameters of body composition, muscle strength and sarcopenia in aged
population from the PREDIMED-PLUS study
Nuria Rosique-Esteban1,2, Nancy Babio1,2, Andrés Díaz-López1,2, Dora Romaguera2,3, J. Alfredo Martínez2,4, Vicente Martin Sanchez5, Helmut Schröder2,6, Ramón Estruch2,7, Josep Vidal8, Pilar Buil-Cosiales2,9, Jadwiga Konieczna2,3, Itziar Abete2,4 and Jordi Salas-Salvadó1,2
Nutrition Unit, University Hospital of Sant Joan de Reus, Department of
Biochemistry and Biotechnology, Pere Virgili Institute for Health
Research, Rovira i Virgili University, Reus, Spain; 2CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; 3Instituto de Investigación Sanitaria de Illes Balears (IdISBa), University Hospital of Son Espases, Palma de Mallorca, Spain; 4Department
of Nutrition, Food Sciences, and Physiology, Center for Nutrition
Research, University of Navarra, Pamplona, Spain. IDISNA Navarra's
Health Research Institute, Pamplona, Spain. IMDEA Food Institute,
Madrid, Spain; 5Grupo de Investigación en
Interacciones Gen-Ambiente y Salud, Universidad de León, León, Spain;
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; 6Cardiovascular
Risk and Nutrition Research Group (CARIN), IMIM (Hospital del Mar
Medical Research Institute), Barcelona, Spain. CIBER Epidemiology and
Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; 7Department
of Internal Medicine, Hospital Clinic, Institut d'Investigació
Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona,
Barcelona, Spain; 8Department of Endocrinology and
Nutrition, Hospital Clínic, Barcelona, Spain; CIBER de Diabetes y
Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos
III, Madrid, Spain; 9Servicio Navarro de
Salud-Osasunbidea Primary Health Care, Navarra, Spain; Navarra Institute
for Health Research, Pamplona, Spain
Aging-related changes in body composition and muscle strength, together
with sarcopenia prevalence, are greatly influenced by physical activity
(PA) and sedentary behaviors (SB). However, these associations have been
barely explored in elder adults at high cardiovascular risk. We
examined the associations of leisure-time PA and SB with sarcopenia
prevalence, body composition and muscle strength in elder adults with
overweight/obesity and metabolic syndrome from the PREDIMED-PLUS trial.
Cross-sectional baseline analysis including 1,539 men and women
(65 ± 5y). Sarcopenia was defined as low muscle mass (lowest
sex-specific tertile for skeletal muscle mass index) plus low muscle
strength (lowest sex-specific tertile for 30-second chair-stand test).
We applied multivariable-logistic regression for the associations of
self-reported leisure-time PA and SB with sarcopenia; and
multivariable-linear regression for the associations with DXA-derived
bone mass, fat mass, lean mass and lower-limb muscle strength.
Inverse associations were observed between sarcopenia and each hourly
increment in total [odds ratio 0.76 (95% confidence interval, 0.63,
0.94)], moderate [0.74 (0.57, 0.97)], vigorous [0.44 (0.23, 0.85)], and
moderate-vigorous PA (MVPA) [0.68 (0.53, 0.87)]. Incrementing 1 h/day
total-PA and MVPA was inversely associated with BMI, waist circumference
(WC), fat mass, and positively associated with bone mass and lower-limb
muscle strength (all P < .05). One h/day increase in total
SB, screen-based SB and TV-viewing was positively associated with BMI,
WC and fat mass. Light-PA was not significantly associated with any
Conclusions: Total-PA and PA at moderate and high
intensities may protect against the prevalence of sarcopenia, have a
beneficial role on body composition and prevent loss of muscle strength.
SB, particularly TV-viewing, may have detrimental effects on body
composition in elderly adults at high cardiovascular risk.
Lean mass is better predictor of bone mineral density than physical fitness in elderly people
Alba Gómez-Cabello1,2,3,4,5, Alejandro Gómez-Bruton2,3,6, Alejandro González-Agüero2,3,4,7, Lucía Sagarra-Romero8,9, José A. Casajús2,3,4,7, Ignacio Ara5,9 and Germán Vicente-Rodríguez2,3,4,7
1Centro Universitario de la Defensa, Zaragoza, Spain; 2GENUD “Growth, Exercise, NUtrition and Development” Research Group, University of Zaragoza, Zaragoza, Spain; 3Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Spain; 4Instituto Agroalimentario de Aragón (IA2); 5Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Spain; 6Universidad Isabel I, Burgos, Spain; 7Faculty
of Health and Sport Science (FCSD), Department of Physiatry and
Nursing, University of Zaragoza, Ronda Misericordia 522001, Huesca,
Spain; 8VALORA Research Group, Universidad San Jorge, Spain; 9GENUD Toledo Research Group, Universidad de Castilla-La Mancha, Toledo, Spain
Within the older population, osteoporosis is a critical age-related
disorder because of the bone loss that occurs during the ageing process
(1). A better understanding of the factors underlying increased bone
fragility in elderly will lead to the definition of appropriate
screening and diagnostic strategies.
Purpose: The aims of
this study were to examine the association of bone mineral density (BMD)
with some of the most widely used physical fitness tests and lean mass
and to determine the differences in bone mass by fitness status in
Methods: Lean mass and BMD (subtotal body, lumbar
spine and femoral neck) were measured with dual energy x-ray
absorptiometry in 204 elderly (144 women) aged 73.4 ± 5.6 years from
Zaragoza (Spain). Physical fitness was evaluated with the Senior Fitness
Test battery and 2 additional tests (static balance and 30-meter
walking speed). The association between physical fitness-related
variables and lean mass with BMD variables was tested by linear
regression adjusting by age and sex. Finally, physical fitness of
osteoporotic participants was compared to that of non-osteoporotic with
age and sex adjusted ANCOVAs.
fitness-related variables did not significantly predict BMD, while lean
mass significantly predicted BMD in all measured sites (4% for the
femoral neck, 9% for the lumbar spine and 6% for the subtotal body; all p < 0.05).
Moreover, no differences were found for physical fitness variables
between osteoporotic and non-osteoporotic participants. Nevertheless,
non-osteoporotic participants presented higher subtotal lean
(39.30 ± 4.33 vs. 36.73 ± 4.27 kg), arms lean (3.91 ± 0.57 vs.
3.82 ± 0.56 kg) and legs lean (12.91 ± 1.59 vs. 12.05 ± 1.56 kg) masses
than osteoporotic participants (all p < 0.05).
BMD is associated to lean mass and not physical fitness in elderly
people. Therefore, BMD may be more susceptible to changes in lean mass
than to changes in physical fitness.
elderly EXERNET multi-centre study has been supported by IMSERSO (104/07
and 147/2011), University of Zaragoza (UZ 2008-BIO-01), Centro
Universitario de la Defensa de Zaragoza (UZCUD2016-BIO-01), Ministerio
de Economía, Industria y Competitividad (DEP2016-78309-R), Biomedical
Research Networking Center on Frailty and Healthy Aging (CIBERFES) and
FEDER funds from the European Union (CB16/10/00477). The authors are
also grateful to all the volunteers and to the Community Center for
Seniors Pedro Laín Entralgo (Zaragoza), whose cooperation and dedication
made this study possible.
- 1Aging and body composition: the sarcopenic obesity in Spain]. Nutr Hosp 2012;27: 22–30., , , , . [
Patients with established cancer cachexia lack the motivation and self-efficacy to undertake regular structured exercise
David Wasley1, Nichola Gale2, Sioned Roberts2, Karianne Backx1,3, Annmarie Nelson4, Robert van Deursen2 and Anthony Byrned4
1Cardiff Metropolitan University, Cardiff School of Sport, Cyncoed Campus, Cardiff, UK; 2Cardiff University, School of Healthcare Sciences, College of Biomedical and Life Sciences, Heath Park, Cardiff, UK; 3Cardiff Centre for Exercise & Health, Cardiff Metropolitan University, Cardiff School of Sport, Cyncoed Campus, Cardiff, UK; 4Marie
Curie Palliative Care Research Centre (MCPCRC), Division of Population
Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff,
Background: Patients with advanced cancer
frequently suffer a decline in activities associated with involuntary
loss of weight and muscle mass (cachexia). This has profound effects on
function and quality of life. Although exercise participation can
maintain physical and psychological function in patients with cancer,
uptake is low in cachectic patients who are underrepresented in exercise
studies. To understand how such patients' experiences influence
exercise participation, we investigated exercise history,
self-confidence, and exercise motivations in patients with established
cancer cachexia, and relationships between relevant variables.
Methods: Lung and gastrointestinal cancer outpatients with established cancer cachexia (n = 196)
completed a questionnaire set exploring exercise history and key
constructs of the Theory of Planned Behaviour relating to perceived
control, psychological adjustment and motivational attitudes.
Patients reported low physical activity levels and few undertook
regular structured exercise. Exercise self-efficacy was very low with
concerns it could worsen symptoms and do harm. Patients showed poor
perceived control and a strong need for approval but received little
advice from healthcare professionals. Preferences were for low intensity
activities, on their own, in the home setting. Logistical regression
analysis revealed no significant factors related to the independent
Conclusions: Frequently employed higher
intensity, group exercise models do not address the motivational and
behavioural concerns of cachectic cancer patients in this study.
Developing exercise interventions which match perceived abilities and
skills are required to address challenges of self-efficacy and perceived
control identified here. Greater engagement of health professionals
with this group in exploring potential benefits of exercise is required.
characteristics are associated with physical functioning during acute
hospitalization and predict functional recovery following discharge in
Rachel R. Deer1, Elena Volpi1 and Sara Nowakowski2
1Sealy Center on Aging, University of Texas Medical Branch, Galveston, TX, USA; 2Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, TX, USA
Poor sleep quality, frequent in older adults, is associated with
reduced physical function and well-being. However, little is known about
the relationship between sleep quality and the recovery of physical
function after hospitalization. Thus, we conducted this study to examine
the association between sleep quality and functional recovery after an
acute hospitalization in community dwelling older adults.
Methods: Older adult patients (N = 27,
mean age = 74 ± 8 years) were recruited during hospitalization (average
length of stay 3.9 days) with Cardiovascular (56%), Pulmonary (22%), or
Metabolic (13%) admission diagnosis. Testing was performed prior to
discharge (baseline) and 1-month post-discharge. Functional performance
was measured using the Short Physical Performance Battery (SPPB)
consisting of three parts: gait, balance and chair rise. Sleep quality
was measured using Pittsburgh Sleep Quality Index (PSQI) global score.
Sleep efficiency and minutes awake after sleep onset was assessed using
actigraphy (Actiwatch 2).
Results: Pearson correlations
revealed significant associations between PSQI and baseline SPPB total
or baseline gait scores. Separate regression models revealed baseline
PSQI score predicted change scores from baseline to 1-month
post-discharge for balance or gait; with a trend for SPPB total scores.
Pearson correlations revealed significant associations between sleep
efficiency and baseline balance, baseline SPPB total, SPPB total change,
SPPB total percent change, balance change, balance percent change, or
gait percent change. Minutes awake after sleep onset was negatively
associated with SPPB percent change score or gait percent change.
Regression found that higher sleep efficiency predicted greater percent
change in SPPB score and higher minutes awake after sleep onset predicts
lower SPPB percent change score.
Conclusions: For older
adults, actigraphy-assessed sleep efficiency and subjectively measured
poorer sleep quality is associated with worse physical functioning
during acute hospitalization. Sleep efficiency, minutes awake after
sleep onset and baseline sleep quality also predicted recovery of
physical functioning following hospitalization. These results suggest
that interventions to improve sleep might help enhance functional
recovery from hospitalization and increase physical function levels.
Resistance training improves lean mass and function in hemodialysis patients
Lorena Cristina Curado Lopes1, João Felipe Mota1, Jonato Prestes2, Raquel Machado Schincaglia1, Débora Mendes Silva1, Nayara Pedatella Queiroz1, Ana Tereza Vaz de Souza Freitas1 and Maria do Rosário Gondim Peixoto1
1Clinical Nutrition and Sports Research Laboratory (LABINCE), Faculty of Nutrition, Federal University of Goias, Brazil; 2Post Graduation Program on Physical Education, Catholic University of Brazilia (UCB), Brazil
Chronic kidney disease (CKD) patients on hemodialysis present a
reduction in muscle mass and functional capacity. These reductions are
associated with greater mortality risk and impairments in quality of
life (QoL). Resistance training (RT) is a viable strategy to attenuate
muscle wasting and loss of strength. The aim of this study was to
investigate the effect of two distinct intradialytic RT protocols on
body composition, sarcopenia prevalence, functional capacity and QoL in
Methods: The study consisted of a 12-week
randomized clinical trial that enrolled 50 participants (age
54.6 ± 11.6) divided into three groups: high-intensity intradialytic RT
(HIG, n = 14); moderate-intensity intradialytic RT (MIG, n = 16) and control (CG, n = 20).
Body composition was assessed by dual-energy X-ray absorptiometry,
functional capacity by the Short Physical Performance Battery score, and
QoL by Kidney Disease Quality of Life Instrument.
Results: After the training period leg lean mass was higher in HIG compared with CG [P = 0.040;
large effect size (ES) = 0.92]. HIG also displayed improvements in QoL
in pain and physical function domains (P = 0.04 for both). Skeletal
muscle index was increased in both RT protocols (P = 0.007; ES = 1.16 and 0.81 for HIG and MIG, respectively), and functional capacity (P = 0.002; ES = 0.33 and 0.52 for HIG and MIG, respectively) when compared to CG.
High-intensity intradialytic RT was associated with gains in lean mass
and QoL compared with lower-intensity while functional capacity and
appendicular muscle mass were improved, regardless of RT intensity.
and extramyocellular lipid, and rVO2 changes following vitamin D
repletion and aerobic training in aged individuals
D. Travis Thomas, Maja Redzic, Mingjun Zhao, David M. Schnell, Hideat Abraha and Guoqiang Yu
University of Kentucky, Lexington, KY, USA
Intramyocellular (IMCL) and extramyocellular lipid (EMCL) is associated
with muscle metabolic dysfunction. The combined effect of vitamin D and
exercise on muscle lipid has not been investigated. We compared the
magnitude of changes in myocellular lipid stores and local muscle oxygen
consumption following combined treatment of vitamin D and aerobic
training (DAT) compared with vitamin D alone (D), aerobic training alone
(AT), and control (Ctl).
Methods: Subjects (>60 YO)
with vitamin D insufficiency (25(OH)D < 32 ng/mL) were randomized to a
double blinded design. Vitamin D3 (10,000 IU × 5 days/week) or placebo
was provided for 12 weeks with 1 additional week (7 consecutive days) of
aerobic training or no training. Gastrocnemius IMCL and EMCL were
measured with magnetic resonance spectroscopy and fat segmentation.
Hybrid near-infrared and diffuse correlative spectroscopy measured local
tissue blood flow, oxygen saturation, and VO2 during and following
(recovery) a gastrocnemius fatiguing protocol. All measurements were
completed at week 0 and at end-study.
Results: Fifteen men
and 16 women completed all measures. Mean age and BMI were 68 ± 6 YO and
25.5 ± 3 kg/m2, respectively. Mean 25(OH)D increased significantly in
subjects receiving vitamin D (41 ± 4 ng/mL) vs. placebo (7 ± 6 ng/mL) (p < 0.05). No group or group by time differences were observed with EMCL (p > 0.05). DAT trended (p = 0.103)
toward the greatest change in IMCL and corresponded to a 18% increase
in rVO2 during full exercise recovery in DAT compared to a 2%, 11%, and
18% reduction in AT, D, and Ctl, respectively.
Vitamin D, when combined with AT, may potentiate the metabolic benefits
of exercise by reducing IMCL and altering tissue-level VO2. Future work
will test the hypothesis that vitamin D promotes muscle lipid
availability for β-oxidation in response to exercise, thereby preventing
lipotoxicity, and improving muscle anabolic sensitivity in populations
at risk for sarcopenia and cachexia.
Supported by NIH grants R21AG046762, UL1TR000117, and T32DK007778-16
of serum testosterone, insulin-like growth factor 1 (IGF-1),
insulin-like growth factor-binding protein-1 (IGFBP-1) and 3 (IGFBP3) on
muscle strength gain after 6 months of progressive resistance training
in older subjects
Antonio Paoli1, Tatiana Moro1,2,3, Antonino Bianco4, Mario Plebani5 and Giuseppe Marcolin1
1Department of Biomedical Sciences, University of Padova, Padova, Italy; 2Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, TX, USA; 3Sealy Center on Aging, University of Texas Medical Branch, Galveston, TX, USA; 4Sport and Exercise Sciences Research Unit, University of Palermo, Palermo, Italy; 5Department of Medicine (DiMed), University of Padova, Padova, Italy
Loss of strength is an important contributor to disability and poor
quality of life in the elderly. Resistance training (RT) is one of the
main treatments suggested to reduce strength and muscle loss during
aging process. Even though basal hormonal levels could play a pivotal
role in determining elderly's muscle mass (Stilling et al., 2017) there
is no agreement about the real role of basal hormonal levels on RT
Methods: We sough to investigate if
basal hormonal levels influence strength improvement after 6 months of
progressive RT in a group of elderly subjects. We analysed 23 subjects
(14 men M and 9 women F), 62.4 ± 3.1 years. We tested lower limb
strength on leg extension before after 6 months of training. We analysed
free fat mass, total testosterone (tT), free testosterone (fT), IGF-1,
IGFBP-1, and IGFBP3 before and after the training period.
No correlation was found between tT, fT, IGF-1, IGFBP-1 and IGFB3 and
free fat mass considering M and F or merged. Moreover, no correlation
was found between fT, tT and strength increase considering men and
women. No correlation was found between IGF-1 and strength. We found a
positive, significant correlation between strength improvement
(p < 0.05, r = 0.435) and basal IGFBP1 concentration
considering men and women merged and a significant negative correlation
between IGFBP3 and strength gains in female (P = 0.006; r = 0.791).
Our results are suggestive of a more complex relationship between
androgens, IGF1, IGFBPs and the response to 6 months of RT. Whilst a
negative correlation between IGFBP1 and muscle mass was found in older
woman (Stilling et al., 2017) our results suggest instead that
higher serum IGFBP1 is related to a better RT response in the elderly
(irrespective to gender) whilst higher IGFBP3 is a predictive factor for
a poor strength increase in older women.
blood flow restriction training in combination with protein
supplementation: a new approach for the prevention and treatment of
Christoph Centner1, Denise Zdzieblik1, Steffen Oesser2, Albert Gollhofer1 and Daniel Koenig1
1Department of Sport Science, University of Freiburg, Germany; 2CRI, Collagen Research Institute GmbH, Kiel, Germany
of skeletal muscle mass and strength is of vital importance in older
age for maintaining musculoskeletal and functional capacity and thus
independence. Recent research has indicated that high-intensity
resistance training (RT) is an effective strategy to counteract the
age-related decline of muscle mass and function. According to the
American College of Sports Medicine training loads of 70–85% of each
individual's one repetition maximum (1RM) are necessary to produce
substantial muscle growth. However, mainly due to comorbidities such as
coronary heart diseases, diabetes and joint or muscle impairments, many
elderlies are not capable of lifting heavy loads. Hence, there is an
increasing need of identifying more suitable training modalities that
combat sarcopenia and other causes of muscular atrophy, particularly in
aged people with serious concomitant diseases. Recently, several studies
have demonstrated that low-intensity exercise (20–40% 1RM) combined
with partial vascular occlusion elicits muscular hypertrophy to a
similar extent to what is typically seen after high-intensity resistance
training. Although the effectiveness blood flow restriction (BFR)
training has been well investigated, no study to date has combined this
training method with an additional nutritional intervention. Besides an
optimal training stimulus, an adequate protein intake has been shown to
stimulate protein synthesis and thus increasing muscle mass and
strength. Previous studies from our research group have demonstrated
that collagen peptides enhance the effects of a 12-week RT regarding its
influence on muscle mass and fat reduction. Therefore, we hypothesize
that BFR training in combination with a protein supplementation is a
promising alternative in order to prevent and treat sarcopenia,
especially in populations for whom high-intensity exercise programs are
contraindicated. We will present the method of BFR training and
additionally discuss possible explanations for improved muscle mass and
function by this concept.
Circulatory levels of oxidative stress markers and BMD in postmenopausal women
Fawaz Azizieh1, Khaled Al Jarallah2, Dia Shehab2, Renu Gupta3 and Raj Raghupathy4
of Mathematics and Natural Sciences, International Centre for Applied
Mathematics and Computational Bioengineering, Gulf University for
Science and Technology, Kuwait; 2Departments of Medicine, Kuwait; 3Radiology, Faculty of Medicine, Kuwait University, Kuwait; 4Microbiology, Faculty of Medicine, Kuwait University, Kuwait
Osteoporosis is a significant health issue which is set to rise
alarmingly worldwide. In addition to some well-characterized factors,
oxidative stress is also suggested to contribute to bone loss in
osteoporosis seen in menopause. Oxidative stress is the result of an
imbalance between the production of reactive oxygen species (ROS) and
the removal of their reactive intermediates. There is much controversy
regarding the possible pathological role of oxidative stress on bone
mineral density (BMD). This study was aimed at measuring serum oxidative
stress parameters i.e., Catalase, Peroxiredoxin 2 (PRX2), Superoxide
dismutase 1 (SOD1), Superoxide dismutase 2 (SOD2) and Thioredoxin (TRx1)
in postmenopausal women with normal, osteopenic and osteoporotic bone
Methods: The study population included 64
post-menopausal women of whom 23 had normal BMD, 38 had osteopenia and
13 had osteoporosis. Serum oxidative stress parameters were measured
using the Multiplex system (Millipore) and read on the Magpex ELISA
Results: Serum levels of Catalase, SOD2 and PRX2
were found significantly lower in postmenopausal women with low BMD
group as compared to women with normal BMD (p = 0.031, 0.044
and 0.041 respectively). These findings support that oxidative stress
plays an important role in pathogenesis of postmenopausal osteoporosis.
However, levels were not significantly different in women with
osteopenia as compared to those with osteoporosis. Furthermore, levels
did not correlate significantly with BMD of the hip or spine.
These data provide insights into the possible role of oxidative stress
on the pathogenesis of postmenopausal osteoporosis. However, the lack of
association between studied oxidative stress markers and BMD may
indicate that osteoporosis may be rather multivariate and complex.
Acknowledgment: This study is supported by Kuwait Foundation of Advancement of Science (KFAS) projects no. 2013–1302-02 and PR17-18SL-01.
and physical changes in normal weight, overweight and obese community
dwelling old adults during a 12 week resistance exercise program
O.G. Geirsdottir1,2, P.V. Jonsson1,3, I. Thorsdottir4 and Alfons Ramel1,2
1The Icelandic Gerontological Research Center, Reykjavik, Iceland; 2Faculty of Food Science and Nutrition, University of Iceland, Reykjavik, Iceland; 3Department of Geriatrics, National University Hospital of Iceland, Reykjavik, Iceland; 4School of Health Sciences, University of Iceland, Reykjavik, Iceland
Resistance exercise is important for the prevention of sarcopenia and
physical dependence of old adults. However, little is known whether
overweight/obesity affect the outcomes of a resistance exercise program.
Methods: Community dwelling Icelandic old adults (N = 236,
73.7 ± 5.7 years) participated in a 12-week resistance exercise
program. Anthropometrics, muscular strength and physical function were
measured at baseline and endpoint. Participants were grouped
retrospectively into normal-, overweight and obese according to
international BMI cut off values. Statistical analyses were corrected
for age and gender.
Results: Of the participants, 22.0%
were normal, 41.4% were overweight and 36.6% were obese. BMI categories
were neither related to drop-out (11.9%) nor to attendance (88.4%). All
groups experienced improvements in outcome measurements, but
improvements in obese individuals were less pronounced compared to
normal weight individuals. There was similar weight gain in the groups
(+0.48 kg, P < 0.001), however, normal weight individuals gained more lean mass (+0.70 kg, P = 0.015), appendicular muscle mass (+0.42 kg, P = 0.007) but tended to loose more fat mass (−0.75 kg, P = 0.081)
as compared to obese. This resulted in a greater change in body fat
percent in normal weight subjects as compared to obese (−1.5%, P = 0.014).
gains in quadriceps strength were similar between groups, but relative
to body weight, normal weight subject gained more than obese subjects
(+0.31 N/kg, P = 0.017). This translated into a greater improvement in 6-minute walk-for-distance (+24. m, P < 0.001) compared to obese subjects. Interestingly, grip strength increased more in obese subjects (2.4 lb, P = 0.020). Timed-up-and-go improved similarly in all groups (−0.64 sec, P < 0.001).
Independently from their body weight status, old adults benefited from a
resistance exercise program in terms of body composition and physical
function. However, obese individuals improved significantly less than
normal weight participants although there was similar attendance to the
exercise classes. Great care has to be taken of obese elderly in order
to maintain their physical independence as long as possible.
- 1Note: aPG-SGA: No cachexia ≠ Cachexia (Male, p-value < 0.001; Female, p-value = 0.001).
- 2Hand grip strength: No cachexia ≠ Cachexia (Male, p-value <0.001; Female, p-value = 0.003).