Article first published online: 2 APR 2018
Stefan D. Anker, Stephan von Haehling, Andrew J.S. Coats
Anker, S. D., von Haehling, S., and Coats, A. J. S. (2018) More variety with the Journal of Cachexia, Sarcopenia and Muscle: JCSM Clinical Reports and JCSM Rapid Communications have both gone live. Journal of Cachexia, Sarcopenia and Muscle, 9: 217–219. doi: 10.1002/jcsm.12298.
Article first published online: 5 FEB 2018
Martin Mücke, Megan Weier, Christopher Carter, Jan Copeland, Louisa Degenhardt, Henning Cuhls, Lukas Radbruch, Winfried Häuser, Rupert Conrad
Systematic review and meta-analysis of cannabinoids in palliative medicineWe provide a systematic review and meta-analysis on the efficacy, tolerability, and safety of cannabinoids in palliative medicine. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, PubMed, Scopus, and http://clinicaltrials.gov, and a selection of cancer journals were searched up until 15th of March 2017. Of the 108 screened studies, nine studies with a total of 1561 participants were included. Overall, the nine studies were at moderate risk of bias. The quality of evidence comparing cannabinoids with placebo was rated according to Grading of Recommendations Assessment, Development, and Evaluation as low or very low because of indirectness, imprecision, and potential reporting bias. In cancer patients, there were no significant differences between cannabinoids and placebo for improving caloric intake (standardized mean differences [SMD]: 0.2 95% confidence interval [CI]: [-0.66, 1.06] P = 0.65), appetite (SMD: 0.81 95% CI: [-1.14, 2.75]; P = 0.42), nausea/vomiting (SMD: 0.21 [-0.10, 0.52] P = 0.19), >30% decrease in pain (risk differences [RD]: 0.07 95% CI: [-0.01, 0.16]; P = 0.07), or sleep problems (SMD: -0.09 95% CI: [-0.62, 0.43] P = 0.72). In human immunodeficiency virus (HIV) patients, cannabinoids were superior to placebo for weight gain (SMD: 0.57 [0.22; 0.92]; P = 0.001) and appetite (SMD: 0.57 [0.11; 1.03]; P = 0.02) but not for nausea/vomiting (SMD: 0.20 [-0.15, 0.54]; P = 0.26). Regarding side effects in cancer patients, there were no differences between cannabinoids and placebo in symptoms of dizziness (RD: 0.03 [-0.02; 0.08]; P = 0.23) or poor mental health (RD: -0.01 [-0.04; 0.03]; P = 0.69), whereas in HIV patients, there was a significant increase in mental health symptoms (RD: 0.05 [0.00; 0.11]; P = 0.05). Tolerability (measured by the number of withdrawals because of adverse events) did not differ significantly in cancer (RD: 1.15 [0.80; 1.66]; P = 0.46) and HIV patients (RD: 1.87 [0.60; 5.84]; P = 0.28). Safety did not differ in cancer (RD: 1.12 [0.86; 1.46]; P = 0.39) or HIV patients (4.51 [0.54; 37.45]; P = 0.32) although there was large uncertainty about the latter reflected in the width of the CI. In one moderate quality study of 469 cancer patients with cancer-associated anorexia, megestrol was superior to cannabinoids in improving appetite, producing >10% weight gain and tolerability. In another study comparing megestrol to dronabinol in HIV patients, megestrol treatment led to higher weight gain without any differences in tolerability and safety. We found no convincing, unbiased, high quality evidence suggesting that cannabinoids are of value for anorexia or cachexia in cancer or HIV patients.
Mücke, M., Weier, M., Carter, C., Copeland, J., Degenhardt, L., Cuhls, H., Radbruch, L., Häuser, W., and Conrad, R. (2018) Systematic review and meta-analysis of cannabinoids in palliative medicine. Journal of Cachexia, Sarcopenia and Muscle, 9: 220-234. doi: 10.1002/jcsm.12273.
Article first published online: 2 NOV 2017
Connie M. Rhee, Seyed-Foad Ahmadi, Csaba P. Kovesdy, Kamyar Kalantar-Zadeh
Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trialsBackground
Recent data pose the question whether conservative management of chronic kidney disease (CKD) by means of a low-protein diet can be a safe and effective means to avoid or defer transition to dialysis therapy without causing protein-energy wasting or cachexia. We aimed to systematically review and meta-analyse the controlled clinical trials with adequate participants in each trial, providing rigorous contemporary evidence of the impact of a low-protein diet in the management of uraemia and its complications in patients with CKD.
We searched MEDLINE (PubMed) and other sources for controlled trials on CKD to compare clinical management of CKD patients under various levels of dietary protein intake or to compare restricted protein intake with other interventions. Studies with similar patients, interventions, and outcomes were included in the meta-analyses.
We identified 16 controlled trials of low-protein diet in CKD that met the stringent qualification criteria including having 30 or more participants. Compared with diets with protein intake of >0.8 g/kg/day, diets with restricted protein intake (<0.8 g/kg/day) were associated with higher serum bicarbonate levels, lower phosphorus levels, lower azotemia, lower rates of progression to end-stage renal disease, and a trend towards lower rates of all-cause death. In addition, very-low-protein diets (protein intake <0.4 g/kg/day) were associated with greater preservation of kidney function and reduction in the rate of progression to end-stage renal disease. Safety and adherence to a low-protein diet was not inferior to a normal protein diet, and there was no difference in the rate of malnutrition or protein-energy wasting.
In this pooled analysis of moderate-size controlled trials, a low-protein diet appears to enhance the conservative management of non-dialysis-dependent CKD and may be considered as a potential option for CKD patients who wish to avoid or defer dialysis initiation and to slow down the progression of CKD, while the risk of protein-energy wasting and cachexia remains minimal.
Rhee, C. M., Ahmadi, S.-F., Kovesdy, C. P., and Kalantar-Zadeh, K. (2017) Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trials. Journal of Cachexia, Sarcopenia and Muscle, 9: 235-245. doi: 10.1002/jcsm.12264.
Article first published online: 17 FEB 2018
Yuhei Hamaguchi, Toshimi Kaido, Shinya Okumura, Atsushi Kobayashi, Hisaya Shirai Siyuan Yao, Shintaro Yagi, Naoko Kamo, Hideaki Okajima, Shinji Uemoto
Proposal for new selection criteria considering pre‐transplant muscularity and visceral adiposity in living donor liver transplantationBackground
The significance of pre‐operative body composition has recently attracted much attention in various diseases. However, cut‐off values for these parameters remain undetermined, and these factors are not currently included in selection criteria for recipients of living donor liver transplantation (LDLT).
Using computed tomography of 657 donors for LDLT, skeletal muscle mass, muscle quality, and visceral adiposity were evaluated by using skeletal muscle mass index (SMI), intramuscular adipose tissue content (IMAC), and visceral‐to‐subcutaneous adipose tissue area ratio (VSR). Sex‐specific cut‐offs for SMI, IMAC, and VSR were determined, and correlations with outcomes after LDLT in 277 recipients were examined with the aim of establishing new selection criteria for LDLT.
On the basis of younger donor data, we determined sex‐specific cut‐off values for low SMI, high IMAC, and high VSR (mean ± 2 standard deviations). Patients with all three factors showed the lowest survival rate after LDLT (1 year survival rate, 41.2%; P < 0.001). On multivariate analysis, low SMI (P = 0.002), high IMAC (P = 0.002), and high VSR (P = 0.001) were identified as independent risk factors for mortality after LDLT. Based on these findings, we have excluded patients showing all three factors (low SMI, high IMAC, and high VSR) as candidates for LDLT since October 2016.
Using cut‐off values determined from healthy donors, we have established new selection criteria for LDLT including body composition, which should improve post‐transplant outcomes.
Hamaguchi, Y., Kaido, T., Okumura, S., Kobayashi, A., Shirai, H., Yao, S., Yagi, S., Kamo, N., Okajima, H., and Uemoto, S. (2018) Proposal for new selection criteria considering pre‐transplant muscularity and visceral adiposity in living donor liver transplantation. Journal of Cachexia, Sarcopenia and Muscle, 9: 246-254. doi: 10.1002/jcsm.12276.
Article first published online: 19 JAN 2018
Tatiana Bering, Kiara G.D. Diniz, Marta Paula P. Coelho, Diego A. Vieira, Maria Marta S. Soares, Adriana M. Kakehasi, Maria Isabel T.D. Correia, Rosângela Teixeira1, Dulciene M.M. Queiroz, Gifone A. Rocha, Luciana D. Silva
Association between pre-sarcopenia, sarcopenia, and bone mineral density in patients with chronic hepatitis CBackground
Preserved skeletal muscle is essential for the maintenance of healthy bone. Loss of bone mineral density (BMD) and muscle strength, considered a predictor of BMD, have been demonstrated in patients with cirrhosis, but they are poorly studied in chronic hepatitis C (CHC) without cirrhosis. Thus, we aimed to evaluate the prevalence of low BMD and its association with body composition, muscle strength, and nutritional status in CHC.
One hundred and four subjects [mean age, 50.5 ± 11.3 years; 75.0% males; 67.3% non-cirrhotic; and 32.7% with compensated cirrhosis] with CHC, prospectively, underwent scanning of the lean tissue, appendicular skeletal muscle mass (ASM), fat mass, lumbar spine, hip, femoral neck, and whole-body BMD by dual-energy X-ray absorptiometry. Muscle strength was assessed by dynamometry. Sarcopenia was defined by the presence of both low, ASM/height2 (ASMI) and low muscle strength according to the European Working Group on Sarcopenia in Older People criteria. The cut-off points for low ASMI and low muscle strength, for women and men, were < 5.45 and < 7.26 kg/m2 and < 20 and < 30 kg, respectively. According to the adopted World Health Organization criteria in men aged > 50 years, the T-score of osteopenia is between -1.0 and -2.49 standard deviation (SD) below the young average value and of osteoporosis is =-2.5 SD below the young normal mean for men, and the Z-score of low bone mass is =-2.0 SD below the expected range in men aged < 50 years and women in the menacme. Nutritional status evaluation was based on the Controlling Nutritional Status score.
Low BMD, low muscle strength, pre-sarcopenia, sarcopenia, and sarcopenic obesity were observed in 34.6% (36/104), 27.9% (29/104), 14.4% (15/104), 8.7% (9/104), and 3.8% (4/104) of the patients, respectively. ASMI was an independent predictor of BMD (P < 0.001). Sarcopenia was independently associated with bone mineral content (P = 0.02) and malnutrition (P = 0.01). In 88.9% of the sarcopenic patients and in all with sarcopenic obesity, BMI was normal. The mid-arm muscle circumference was positively correlated with ASMI (r = 0.88; P < 0.001).
This is the first study to demonstrate that ASM is an independent predictor of BMD in CHC. Mid-arm muscle circumference coupled with handgrip strength testing should be incorporated into routine clinical practice to detect low muscle mass, which may be underdiagnosed when only BMI is used. These findings may influence clinical decision-making and contribute to the development of effective strategies to screen the musculoskeletal abnormalities in CHC patients, independently of the stage of the liver disease.
Bering, T., Diniz, K. G. D., Coelho, M. P. P., Vieira, D. A., Soares, M. M. S., Kakehasi, A. M., Correia, M. I. T. D., Teixeira, R., Queiroz, D. M. M., Rocha, G. A., and Silva, L. D. (2018) Association between pre-sarcopenia, sarcopenia, and bone mineral density in patients with chronic hepatitis C. Journal of Cachexia, Sarcopenia and Muscle, 9: 255-268. doi: 10.1002/jcsm.12269.
Article first published online: 19 JAN 2018
Fanny Buckinx, Francesco Landi, Matteo Cesari, Roger A. Fielding, Marjolein Visser, Klaus Engelke, Stefania Maggi, Elaine Dennison, Nasser M. Al-Daghri, Sophie Allepaerts, Jurgen Bauer, Ivan Bautmans, Maria Luisa Brandi, Olivier Bruyère, Tommy Cederholm, Francesca Cerreta, Antonio Cherubini, Cyrus Cooper, Alphonso Cruz-Jentoft, Eugene McCloskey, Bess Dawson-Hughes, Jean-Marc Kaufman, Andrea Laslop, Jean Petermans, Jean-Yves Reginster, René Rizzoli, Sian Robinson, Yves Rolland, Ricardo Rueda, Bruno Vellas, John A. Kanis
Pitfalls in the measurement of muscle mass: a need for a reference standardBackground
All proposed definitions of sarcopenia include the measurement of muscle mass, but the techniques and threshold values used vary. Indeed, the literature does not establish consensus on the best technique for measuring lean body mass. Thus, the objective measurement of sarcopenia is hampered by limitations intrinsic to assessment tools. The aim of this study was to review the methods to assess muscle mass and to reach consensus on the development of a reference standard.
Literature reviews were performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis working group on frailty and sarcopenia. Face-to-face meetings were organized for the whole group to make amendments and discuss further recommendations.
A wide range of techniques can be used to assess muscle mass. Cost, availability, and ease of use can determine whether the techniques are better suited to clinical practice or are more useful for research. No one technique subserves all requirements but dual energy X-ray absorptiometry could be considered as a reference standard (but not a gold standard) for measuring muscle lean body mass.
Based on the feasibility, accuracy, safety, and low cost, dual energy X-ray absorptiometry can be considered as the reference standard for measuring muscle mass.
Buckinx, F., Landi, F., Cesari, M., Fielding, R. A., Visser, M., Engelke, K., Maggi, S., Dennison, E., Al-Daghri, N. M., Allepaerts, S., Bauer, J., Bautmans, I., Brandi, M. L., Bruyère, O., Cederholm, T., Cerreta, F., Cherubini, A., Cooper, C., Cruz-Jentoft, A., McCloskey, E., Dawson-Hughes, B., Kaufman, J.-M., Laslop, A., Petermans, J., Reginster, J.-Y., Rizzoli, R., Robinson, S., Rolland, Y., Rueda, R., Vellas, B., and Kanis, J. A. (2018) Pitfalls in the measurement of muscle mass: a need for a reference standard. Journal of Cachexia, Sarcopenia and Muscle, 9: 269-278. doi: 10.1002/jcsm.12268.
Article first published online: 24 JAN 2018
Giovanna Distefano, Robert A. Standley, Xiaolei Zhang, Elvis A. Carnero, Fanchao Yi, Heather H. Cornnell, Paul M. Coen
Physical activity unveils the relationship between mitochondrial energetics, muscle quality, and physical function in older adultsBackground
The concept of mitochondrial dysfunction in ageing muscle is highly controversial. In addition, emerging evidence suggests that reduced muscle oxidative capacity and efficiency underlie the aetiology of mobility loss in older adults. Here, we hypothesized that studying well-phenotyped older cohorts across a wide range of physical activity would unveil a range of mitochondrial function in skeletal muscle and in turn allow us to more clearly examine the impact of age per se on mitochondrial energetics. This also enabled us to more clearly define the relationships between mitochondrial energetics and muscle lipid content with clinically relevant assessments of muscle and physical function.
Thirty-nine volunteers were recruited to the following study groups: young active (YA, n = 2 women/8 men, age = 31.2 ± 5.4 years), older active (OA, n = 2 women/8 men, age = 67.5 ± 2.7 years), and older sedentary (OS, n = 8 women/11 men, age = 70.7 ± 4.7 years). Participants completed a graded exercise test to determine fitness (VO2peak), a submaximal exercise test to determine exercise efficiency, and daily physical activity was recorded using a tri-axial armband accelerometer. Mitochondrial energetics were determined by (i) 31P magnetic resonance spectroscopy and (ii) respirometry of fibre bundles from vastus lateralis biopsies. Quadriceps function was assessed by isokinetic dynamometry and physical function by the short physical performance battery and stair climb test.
Daily physical activity energy expenditure was significantly lower in OS, compared with YA and OA groups. Despite fitness being higher in YA compared with OA and OS, mitochondrial respiration, maximum mitochondrial capacity, Maximal ATP production/Oxygen consumption (P/O) ratio, and exercise efficiency were similar in YA and OA groups and were significantly lower in OS. P/O ratio was correlated with exercise efficiency. Time to complete the stair climb and repeated chair stand tests were significantly greater for OS. Interestingly, maximum mitochondrial capacity was related to muscle contractile performance and physical function.
Older adults who maintain a high amount of physical activity have better mitochondrial capacity, similar to highly active younger adults, and this is related to their better muscle quality, exercise efficiency, and physical performance. This suggests that mitochondria could be an important therapeutic target for sedentary ageing associated conditions including sarcopenia, dynapenia, and loss of physical function.
Distefano, G., Standley, R. A., Zhang, X., Carnero, E. A., Yi, F., Cornnell, H. H., and Coen, P. M. (2018) Physical activity unveils the relationship between mitochondrial energetics, muscle quality, and physical function in older adults. Journal of Cachexia, Sarcopenia and Muscle, 9: 279-294. doi: 10.1002/jcsm.12272.
Article first published online: 21 DEC 2017
Éadaoin B. Ní Bhuachalla, Louise E. Daly1, Derek G. Power, Samantha J. Cushen, Peter MacEneaney, Aoife M. Ryan
Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition?Background
Nutrition screening on admission to hospital is mandated in many countries, but to date, there is no consensus on which tool is optimal in the oncology setting. Wasting conditions such as cancer cachexia (CC) and sarcopenia are common in cancer patients and negatively impact on outcomes; however, they are often masked by excessive adiposity. This study aimed to inform the application of screening in cancer populations by investigating whether commonly used nutritional screening tools are adequately capturing nutritionally vulnerable patients, including those with abnormal body composition phenotypes (CC, sarcopenia, and myosteatosis).
A prospective study of ambulatory oncology outpatients presenting for chemotherapy was performed. A detailed survey incorporating clinical, nutritional, biochemical, and quality of life data was administered. Participants were screened for malnutrition using the Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST), and the Nutritional Risk Index (NRI). Computed tomography (CT) assessment of body composition was performed to diagnose CC, sarcopenia, and myosteatosis according to consensus criteria.
A total of 725 patients (60% male, median age 64 years) with solid tumours participated (45% metastatic disease). The majority were overweight/obese (57%). However, 67% were losing weight, and CT analysis revealed CC in 42%, sarcopenia in 41%, and myosteatosis in 46%. Among patients with CT-identified CC, the MUST, MST, and NRI tools categorized 27%, 35%, and 7% of them as ‘low nutritional risk’, respectively. The percentage of patients with CT-identified sarcopenia and myosteatosis that were categorised as ‘low nutritional risk’ by MUST, MST and NRI were 55%, 61%, and 14% and 52%, 50%, and 11%, respectively. Among these tools, the NRI was most sensitive, with scores <97.5 detecting 85.8%, 88.6%, and 92.9% of sarcopenia, myosteatosis, and CC cases, respectively. Using multivariate Cox proportional hazards models, NRI score < 97.5 predicted greater mortality risk (hazard ratio 1.8, confidence interval: 1.2–2.8, P = 0.007).
High numbers of nutritionally vulnerable patients, with demonstrated abnormal body composition phenotypes on CT analysis, were misclassified by MUST and MST. Caution should be exercised when categorizing the nutritional risk of oncology patients using these tools. NRI detected the majority of abnormal body composition phenotypes and independently predicted survival. Of the tools examined, the NRI yielded the most valuable information from screening and demonstrated usefulness as an initial nutritional risk grading system in ambulatory oncology patients.
Ní Bhuachalla, É. B., Daly, L. E., Power, D. G., Cushen, S. J., MacEneaney, P., and Ryan, A. M. (2017) Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition?. Journal of Cachexia, Sarcopenia and Muscle, 9: 295-305. doi: 10.1002/jcsm.12258.
Article first published online: 25 JAN 2018
Ting Zhou, Bangyan Wang, Huiquan Liu, Kaixiang Yang, Sudip Thapa, Haowen Zhang, Lu Li, Shiying Yu
Development and validation of a clinically applicable score to classify cachexia stages in advanced cancer patientsBackground
Cachexia is a multifactorial syndrome that is highly prevalent in advanced cancer patients and leads to progressive functional impairments. The classification of cachexia stages is essential for diagnosing and treating cachexia. However, there is a lack of simple tools with good discrimination for classifying cachexia stages. Therefore, our study aimed to develop a clinically applicable cachexia staging score (CSS) and validate its discrimination of clinical outcomes for different cachexia stages.
Advanced cancer patients were enrolled in our study. A CSS comprising the following five components was developed: weight loss, a simple questionnaire of sarcopenia (SARC-F), Eastern Cooperative Oncology Group, appetite loss, and abnormal biochemistry. According to the CSS, patients were classified into non-cachexia, pre-cachexia, cachexia, and refractory cachexia stages, and clinical outcomes were compared among the four groups.
Of the 297 participating patients, data from 259 patients were ultimately included. Based on the CSS, patients were classified into non-cachexia (n = 69), pre-cachexia (n = 68), cachexia (n = 103), and refractory cachexia (n = 19) stages. Patients with more severe cachexia stages had lower skeletal muscle indexes (P = 0.002 and P = 0.004 in male and female patients, respectively), higher prevalence of sarcopenia (P = 0.017 and P = 0.027 in male and female patients, respectively), more severe symptom burden (P < 0.001), poorer quality of life (P < 0.001 for all subscales except social well-being), and shorter survival times (P < 0.001).
The CSS is a simple and clinically applicable tool with excellent discrimination for classifying cachexia stages. This score is extremely useful for the clinical treatment and prognosis of cachexia and for designing clinical trials.
Zhou, T., Wang, B., Liu, H., Yang, K., Thapa, S., Zhang, H., Li, L., and Yu, S. (2018) Development and validation of a clinically applicable score to classify cachexia stages in advanced cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 9: 306-314. doi: 10.1002/jcsm.12275.
Article first published online: 9 JAN 2018
Louise E. Daly, Éadaoin B. Ní Bhuachalla, Derek G. Power, Samantha J. Cushen, Karl James, Aoife M. Ryan
Loss of skeletal muscle during systemic chemotherapy is prognostic of poor survival in patients with foregut cancerBackground
Malnutrition, weight loss, and muscle wasting are common in patients with foregut cancers (oesophagus, stomach, pancreas, liver, and bile ducts) and are associated with adverse clinical outcomes. However, little is known about the changes in body composition that occur in these patients during chemotherapy and its impacts clinical outcomes.
Patients and methods
A prospective study of adult foregut cancer patients undergoing chemotherapy between 2012 and 2016 was conducted. Computed tomography images were evaluated for cross-sectional skeletal muscle area (SMA) and adipose tissue area (ATA) at two time points [interval 118 days (IQR 92–58 days)]. Longitudinal changes in SMA and ATA were examined using paired t-tests. Sarcopenia and low muscle attenuation (MA) were defined using published cut-points. Cox proportional hazards models were used to estimate mortality hazard ratios for key predictors.
A total of 225 foregut cancer patients were included (67% male, median age 66 years). At baseline, 40% were sarcopenic, 49% had low MA, and 62% had cancer cachexia. Longitudinal analysis (n = 163) revealed significant reductions in SMA [-6.1 cm2 (3.9%)/100 days, P < 0.001]. Patients treated with neoadjuvant chemotherapy experienced greater losses in SMA and skeletal muscle mass compared with patients receiving palliative chemotherapy [-6.6 cm2 (95%, confidence interval, CI: -10.2 to -3.1), P < 0.001 and -1.2 kg (95% CI: -1.8 to -0.5), P < 0.001, respectively]. Neither sarcopenia nor low MA at baseline was associated with reduced survival. A loss of SMA >6.0%/100 days (highest fourth) independently predicted overall survival in patients receiving palliative chemotherapy [hazard ratio: 2.66, (95% CI: 1.42 to 4.97), P = 0.002].
Patients with foregut cancers, particularly those treated with neoadjuvant chemotherapy, experience significant losses of muscle during chemotherapy. A high level of SMA loss is prognostic of reduced survival in patients treated with palliative chemotherapy. Multimodal interventions to stabilize or increase muscle mass and influence outcome warrant further investigation.
Daly, L. E., Ní Bhuachalla, É. B., Power, D. G., Cushen, S. J., James, K., and Ryan, A. M. (2018) Loss of skeletal muscle during systemic chemotherapy is prognostic of poor survival in patients with foregut cancer. Journal of Cachexia, Sarcopenia and Muscle, 9. 315-325. doi: 10.1002/jcsm.12267.
Article first published online: 5 FEB 2018
Moon Hyung Choi, Seung Bae Yoon, Kyungjin Lee, Meiying Song, In Seok Lee, Myung Ah Lee, Tae Ho Hong, Myung-Gyu Choi
Preoperative sarcopenia and post-operative accelerated muscle loss negatively impact survival after resection of pancreatic cancerBackground
Sarcopenia and post-operative accelerated muscle loss leading to cachexia are commonly observed in patients with pancreatic cancer. This study aimed to assess the influence of body compositions and post-operative muscle change on survival of patients with surgically treated pancreatic cancer.
We analysed data of patients diagnosed with pancreatic adenocarcinoma who underwent surgery from 2008 to 2015. Skeletal muscle areas, muscle attenuation, and visceral and subcutaneous adipose tissue areas were measured from two sets of computed tomography images at L3 vertebral levels. In addition, muscle change was calculated from images obtained before and after cancer resection. We set our own cut-off values of various body compositions based on sex-specific tertiles.
A total of 180 patients were analysed. Patients with perioperative sarcopenia (n = 60) showed poorer overall survival than those without perioperative sarcopenia (P = 0.031). Fifty (28.6%) patients with accelerated muscle loss after surgery (>10%/60 days) had poorer survival compared with the others (P = 0.029). Sarcopenia (hazard ratio, 1.79: 95% confidence interval, 1.20–2.65] and post-operative muscle change (%/60 days) (hazard ratio, 0.94: 95% confidence interval, 0.92–0.96) were identified as significant predictors of survival on multivariable analyses.
Preoperative sarcopenia identified on CT scan was associated with poor overall survival in patients with pancreatic cancer following surgery. Accelerated muscle loss after surgery also negatively impacted survival in pancreatic cancer patients.
Choi, M. H., Yoon, S. B., Lee, K., Song, M., Lee, I. S., Lee, M. A., Hong, T. H., and Choi, M.-G. (2018) Preoperative sarcopenia and post-operative accelerated muscle loss negatively impact survival after resection of pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle, 9: 326-334. doi: 10.1002/jcsm.12274.
Article first published online: 16 DEC 2017
Allan F. Pagano, Thomas Brioche, Coralie Arc-Chagnaud, Rémi Demangel, Angèle Chopard, Guillaume Py
Short-term disuse promotes fatty acid infiltration into skeletal muscleBackground
Many physiological and/or pathological conditions lead to muscle deconditioning, a well-described phenomenon characterized by a loss of strength and muscle power mainly due to the loss of muscle mass. Fatty infiltrations, or intermuscular adipose tissue (IMAT), are currently well-recognized components of muscle deconditioning. Despite the fact that 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 favour IMAT development, deciphering the early processes of muscle disuse is of great importance before implementing strategies to limit IMAT deposition.
In our study, we took advantage of the dry immersion (DI) model of severe muscle inactivity to induce rapid muscle deconditioning during a short period. During the DI, healthy adult men (n = 12; age: 32 ± 5) remained strictly immersed, in a supine position, in a controlled thermo-neutral water bath. Skeletal muscle biopsies were obtained from the vastus lateralis 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%). Moreover, protein expression levels of two key markers commonly used to assess IMAT, perilipin, and fatty acid binding protein 4, were upregulated. We also observed an increase in the C/EBPa and PPAR? 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) represent the population that appears to play a major role in IMAT development. In our study, we showed an increase in the protein expression of PDGFRa, the specific cell surface marker of FAPs, in response to 3 days of DI. It is well recognized that an unfavourable 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.
Pagano, A. F., Brioche, T., Arc-Chagnaud, C., Demangel, R., Chopard, A., and Py, G. (2017) Short-term disuse promotes fatty acid infiltration into skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, 9: 335-347. doi: 10.1002/jcsm.12259.
Article first published online: 20 FEB 2018
Mónica Patricia, Cala María Teresa Agulló‐Ortuño, Elena Prieto‐García, Carolina González‐Riano, Lucía Parrilla‐Rubio, Coral Barbas, Carmen Vanesa Díaz‐García, Antonia García, Cristina Pernaut, Jorge Adeva, María Carmen Riesco, Francisco Javier Rupérez, Jose Antonio, Lopez‐Martin
Multiplatform plasma fingerprinting in cancer cachexia: a pilot observational and translational studyBackground
Cachexia is a metabolic syndrome that affects up to 50–80% of cancer patients. The pathophysiology is characterized by a variable combination of reduced food intake and abnormal metabolism, including systemic inflammation and negative protein and energy balance. Despite its high clinical significance, defined diagnostic criteria and established therapeutic strategies are lacking. The ‘omics’ technologies provide a global view of biological systems. We hypothesize that blood‐based metabolomics might identify findings in cachectic patients that could provide clues to gain knowledge on its pathophysiology, and eventually postulate new therapeutic strategies.
This is a cross‐sectional observational study in two cohorts of cancer patients, with and without cachexia. Patients were consecutively recruited from routine clinical practice of a General Oncology Department at ‘12 de Octubre’ University Hospital. Selected clinical and biochemical features were collected. Blood metabolite fingerprinting was performed using three analytical platforms, gas chromatography coupled to mass spectrometry (GC–MS), capillary electrophoresis coupled to mass spectrometry (CE–MS), and liquid chromatography coupled to mass spectrometry (LC–MS). Besides, we performed pathway‐based metabolite analyses to obtain more information on biological functions.
A total of 15 subjects were included in this study, 8 cachectic and 7 non‐cachectic patients. Metabolomic analyses were able to correctly classify their samples in 80% (GC–MS), 97% (CE–MS), 96% [LC–MS (positive mode)], and 89% [LC–MS (negative mode)] of the cases. The most prominent metabolic alteration in plasma of cachectic patients was the decrease of amino acids and derivatives [especially arginine, tryptophan, indolelactic acid, and threonine, with 0.4‐fold change (FC) compared with non‐cachectic patients], along with the reduction of glycerophospholipids [mainly lysophosphatidylcholines(O‐16:0) and lysophosphatidylcholines(20:3) sn‐1, FC = 0.1] and sphingolipids [SM(d30:0), FC = 0.5]. The metabolite with the highest increase was cortisol (FC = 1.6). Such alterations suggest a role of the following metabolic pathways in the pathophysiology of cancer cachexia: arginine and proline metabolism; alanine, aspartate, and glutamate metabolism; phenylalanine metabolism; lysine degradation; aminoacyl‐tRNA biosynthesis; fatty acid elongation in mitochondria; tricarboxylic acids cycle; among others.
These findings suggest that plasma amino acids and lipids profiling has great potential to find the mechanisms involved in the pathogenesis of cachexia. Metabolic profiling of plasma from cancer patients show differences between cachexia and non‐cachexia in amino acids and lipids that might be related to mechanisms involved in its pathophysiology. A better understanding of these mechanisms might identify novel therapeutic approaches to palliate this unmet medical condition.
Cala, M. P., Agulló‐Ortuño, M. T., Prieto‐García, E., González‐Riano, C., Parrilla‐Rubio, L., Barbas, C., Díaz‐García, C. V., García, A., Pernaut, C., Adeva, J., Riesco, M. C., Rupérez, F. J., and Lopez‐Martin, J. A. (2018) Multiplatform plasma fingerprinting in cancer cachexia: a pilot observational and translational study. Journal of Cachexia, Sarcopenia and Muscle, 9: 348-357. doi: 10.1002/jcsm.12270.
Article first published online: 7 JAN 2018
Erin E. Talbert, Heather L. Lewis, Matthew R. Farren, Mitchell L. Ramsey, Jeffery M. Chakedis, Priyani Rajasekera, Ericka Haverick, Angela Sarna, Mark Bloomston, Timothy M. Pawlik, Teresa A. Zimmers, Gregory B. Lesinski, Phil A. Hart, Mary E. Dillhoff, Carl R. Schmidt, Denis C. Guttridge
Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-naïve pancreatic cancer patientsBackground
Cancer-associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer-induced cachexia in patients with earlier stages of disease.
A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high-sensitivity multiplex was used for increased sensitivity for nine cytokines.
Resectable pancreatic cancer patients with cachexia had low levels of canonical pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein-1 (MCP-1) was increased in treatment-naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were found to be decreased in the same cohort of treatment-naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers.
Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment-naïve patients have higher levels of MCP-1, suggesting that MCP-1 may be useful as a biomarker of cancer cachexia.
Talbert, E. E., Lewis, H. L., Farren, M. R., Ramsey, M. L., Chakedis, J. M., Rajasekera, P., Haverick, E., Sarna, A., Bloomston, M., Pawlik, T. M., Zimmers, T. A., Lesinski, G. B., Hart, P. A., Dillhoff, M. E., Schmidt, C. R., and Guttridge, D. C. (2017) Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-naïve pancreatic cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 9: 358-368. doi: 10.1002/jcsm.12251.
Article first published online: 7 DEC 2017
Justin P. Hardee, Brittany R. Counts, Song Gao, Brandon N. VanderVeen, Dennis K. Fix, Ho-Jin Koh, James A. Carson
Inflammatory signalling regulates eccentric contraction-induced protein synthesis in cachectic skeletal muscleBackground
Skeletal muscle responds to eccentric contractions (ECC) with an anabolic response that involves the induction of protein synthesis through the mechanistic target of rapamycin complex 1. While we have reported that repeated ECC bouts after cachexia initiation attenuated muscle mass loss and inflammatory signalling, cachectic muscle's capacity to induce protein synthesis in response to ECC has not been determined. Therefore, we examined cachectic muscle's ability to induce mechano-sensitive pathways and protein synthesis in response to an anabolic stimulus involving ECC and determined the role of muscle signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signalling on ECC-induced anabolic signalling.
Mechano-sensitive pathways and anabolic signalling were examined immediately post or 3 h after a single ECC bout in cachectic male ApcMin/+ mice (n = 17; 16 ± 1% body weight loss). Muscle STAT3/NFκB regulation of basal and ECC-induced anabolic signalling was also examined in an additional cohort of ApcMin/+ mice (n = 10; 16 ± 1% body weight loss) that received pyrrolidine dithiocarbamate 24 h prior to a single ECC bout. In all experiments, the left tibialis anterior performed ECC while the right tibialis anterior served as intra-animal control. Data were analysed by Student's t-test or two-way repeated measures analysis of variance with Student-Newman-Keuls post-hoc when appropriate. The accepted level of significance was set at P < 0.05 for all analysis.
ApcMin/+ mice exhibited a cachectic muscle signature demonstrated by perturbed proteostasis (Ribosomal Protein S6 (RPS6), P70S6K, Atrogin-1, and Muscle RING-finger protein-1 (MuRF1)), metabolic (adenosine monophosphate-activated protein kinase, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and Cytochrome c oxidase subunit IV (COXIV)), and inflammatory (STAT3, NFκB, extracellular signal-regulated kinases 1 and 2, and P38) signalling pathway regulation. Nonetheless, mechano-sensitive signalling pathways (P38, extracellular signal-regulated kinases 1 and 2, and Protein kinase B (AKT)) were activated immediately post-ECC irrespective of cachexia. While cachexia did not attenuate ECC-induced P70S6K activation, the protein synthesis induction remained suppressed compared with healthy controls. However, muscle STAT3/NFκB inhibition increased basal and ECC-induced protein synthesis in cachectic ApcMin/+ mice.
These studies demonstrate that mechano-sensitive signalling is maintained in cachectic skeletal muscle, but chronic STAT3/NFκB signalling serves to attenuate basal and ECC-induced protein synthesis.
Hardee, J. P., Counts, B. R., Gao, S., VanderVeen, B. N., Fix, D. K., Koh, H.-J., and Carson, J. A. (2017) Inflammatory signalling regulates eccentric contraction-induced protein synthesis in cachectic skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, 9: 369-383. doi: 10.1002/jcsm.12271.
Article first published online: 5 FEB 2018
Tatiane Gorski, Sebastian Mathes, Jan Krützfeldt
Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal controlBackground
Intramuscular fatty infiltration is generally associated with the accumulation of white adipocytes in skeletal muscle and unfavourable metabolic outcomes. It is, however, still unclear whether intramuscular adipocytes could also acquire a brown-like phenotype. Here, we detected intramuscular expression of brown adipocyte markers during fatty infiltration in an obesity-resistant mouse strain and extensively compared the potential of two different stem cell populations residing in skeletal muscle to differentiate into brown-like adipocytes.
Fatty infiltration was induced using intramuscular glycerol or cardiotoxin injection in the tibialis anterior muscles of young or aged 129S6/SvEvTac (Sv/129) mice or interleukin-6 (IL-6) knockout mice, and the expression of general and brown adipocyte markers was assessed after 4 weeks. Fibro/adipogenic progenitors (FAPs) and myogenic progenitors were prospectively isolated using fluorescence-activated cell sorting from skeletal muscle of male and female C57Bl6/6J and Sv/129 mice, and monoclonal and polyclonal cultures were treated with brown adipogenic medium. Additionally, FAPs were differentiated with medium supplemented or not with triiodothyronine.
Although skeletal muscle expression of uncoupling protein 1 (Ucp1) was barely detectable in uninjected tibialis anterior muscle, it was drastically induced following intramuscular adipogenesis in Sv/129 mice and further increased in response to beta 3-adrenergic stimulation. Intramuscular Ucp1 expression did not depend on IL-6 and was preserved in aged skeletal muscle. Myogenic progenitors did not form adipocytes neither in polyclonal nor monoclonal cultures. Fibro/adipogenic progenitors, on the other hand, readily differentiated into brown-like, UCP1+ adipocytes. Uncoupling protein 1 expression in differentiated FAPs was regulated by genetic background, sex, and triiodothyronine treatment independently of adipogenic differentiation levels.
Intramuscular adipogenesis is associated with increased Ucp1 expression in skeletal muscle from obesity-resistant mice. Fibro/adipogenic progenitors provide a likely source for intramuscular adipocytes expressing UCP1 under control of both genetic and hormonal factors. Therefore, FAPs constitute a possible target for therapies aiming at the browning of intramuscular adipose tissue and the metabolic improvement of skeletal muscle affected by fatty infiltration.
Gorski, T., Mathes, S., and Krützfeldt, J. (2018) Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control. Journal of Cachexia, Sarcopenia and Muscle, 9: 384-399. doi: 10.1002/jcsm.12277.
Article first published online: 7 DEC 2017
Martin Connolly, Richard Paul, Roser Farre-Garros, Samantha A. Natanek, Susannah Bloch, Jen Lee, Jose P. Lorenzo, Harnish Patel, Cyrus Cooper, Avan A. Sayer, Stephen J. Wort, Mark Griffiths, Michael I. Polkey, Paul R. Kemp
miR-424-5p reduces ribosomal RNA and protein synthesis in muscle wastingBackground
A loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis, so changes in the control of ribosome synthesis are potential contributors to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR-424-5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD).
Targets of miR-424-5p were identified by Argonaute2 pull down, and the effects of the miRNA on RNA and protein expression were determined by quantitative polymerase chain reaction and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over-expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by quantitative polymerase chain reaction in patients with COPD and intensive care unit (ICU)-acquired weakness and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study.
Pull-down assays showed that miR-424-5p bound to messenger RNAs encoding proteins associated with muscle protein synthesis. The most highly enriched messenger RNAs encoded proteins required for the Pol I RNA pre-initiation complex required for ribosomal RNA (rRNA) transcription, (PolR1A and upstream binding transcription factor). In vitro, miR-424-5p reduced the expression of these RNAs, reduced rRNA levels, and inhibited protein synthesis. In mice, over-expression of miR-322 (rodent miR-424 orthologue) caused fibre atrophy and reduced upstream binding transcription factor expression and rRNA levels. In humans, elevated miR-424-5p associated with markers of disease severity in COPD (FEV1%), in patients undergoing aortic surgery (LVEF%), and in patients with ICU-acquired weakness (days in ICU). In patients undergoing aortic surgery, preoperative miR-424-5p expression in skeletal muscle was associated with muscle loss over the following 7 days.
These data suggest that miR-424-5p regulates rRNA synthesis by inhibiting Pol I pre-initiation complex formation. Increased miR-424-5p expression in patients with conditions associated with muscle wasting is likely to contribute to the inhibition of protein synthesis and loss of muscle mass.
Connolly, M., Paul, R., Farre-Garros, R., Natanek, S. A., Bloch, S., Lee, J., Lorenzo, J. P., Patel, H., Cooper, C., Sayer, A. A., Wort, S. J., Griffiths, M., Polkey, M. I., and Kemp, P. R. (2017) miR-424-5p reduces ribosomal RNA and protein synthesis in muscle wasting. Journal of Cachexia, Sarcopenia and Muscle, 9: 400-416. doi: 10.1002/jcsm.12266.
Article first published online: 11 DEC 2017
Juha J. Hulmi, Tuuli A. Nissinen, Markus Räsänen, Joni Degerman, Juulia H. Lautaoja, Karthik Amudhala Hemanthakumar, Janne T. Backman, Olli Ritvos, Mika Silvennoinen, Riikka Kivelä
Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscleBackground
Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown.
The effects of DOX treatment with or without pre-treatment with soluble ACVR2B-Fc (sACVR2B-Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)-treated controls, (2) DOX-treated mice (DOX), and (3) DOX-treated mice administered with sACVR2B-Fc during the experiment (DOX + sACVR2B-Fc). DOX was administered with a cumulative dose of 24 mg/kg during 2 weeks to investigate cachexia outcome in the heart and skeletal muscle. To understand similarities and differences between skeletal and cardiac muscles in their responses to chemotherapy, the tissues were collected 20 h after a single DOX (15 mg/kg) injection and analysed with genome-wide transcriptomics and mRNA and protein analyses. The combination group was pre-treated with sACVR2B-Fc 48 h before DOX administration. Major findings were also studied in mice receiving only sACVR2B-Fc.
The DOX treatment induced similar (~10%) wasting in skeletal muscle and the heart. However, transcriptional changes in response to DOX were much greater in skeletal muscle. Pathway analysis and unbiased transcription factor analysis showed that p53-p21-REDD1 is the main common pathway activated by DOX in both skeletal and cardiac muscles. These changes were attenuated by blocking ACVR2B ligands especially in skeletal muscle. Tceal7 (3-fold to 5-fold increase), transferrin receptor (1.5-fold increase), and Ccl21 (0.6-fold to 0.9-fold decrease) were identified as novel genes responsive to blocking ACVR2B ligands. Overall, at the transcriptome level, ACVR2B ligand blocking had only minor influence in the heart while it had marked effects in skeletal muscle. The same was also true for the effects on tissue wasting. This may be explained in part by about 18-fold higher gene expression of myostatin in skeletal muscle compared with the heart.
Cardiac and skeletal muscles display similar atrophy after DOX treatment, but the mechanisms for this may differ between the tissues. The present results suggest that p53-p21-REDD1 signalling is the main common DOX-activated pathway in these tissues and that blocking activin receptor ligands attenuates this response, especially in skeletal muscle supporting the overall stronger effects of this treatment in skeletal muscles.
Hulmi, J. J., Nissinen, T. A., Räsänen, M., Degerman, J., Lautaoja, J. H., Hemanthakumar, K. A., Backman, J. T., Ritvos, O., Silvennoinen, M., and Kivelä, R. (2017) Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. Journal of Cachexia, Sarcopenia and Muscle, 9: 417-432. doi: 10.1002/jcsm.12265.