Article first published online:  04 February 2019

Debora Basile, Annamaria Parnofiello, Maria Grazia Vitale, Francesco Cortiula, Lorenzo Gerratana, Valentina Fanotto, Camilla Lisanti, Giacomo Pelizzari, Elena Ongaro, Michele Bartoletti, Silvio Ken Garattini, Victoria Josephine Andreotti, Anna Bacco, Donatella Iacono, Marta Bonotto, Mariaelena Casagrande, Paola Ermacora, Fabio Puglisi, Nicoletta Pella, Gianpiero Fasola, Giuseppe Aprile
Giovanni G. Cardellino

The IMPACT study: early loss of skeletal muscle mass in advanced pancreatic cancer patients
Background
Pancreatic cancer (PC) patients have multiple risk factors for sarcopenia and loss of skeletal muscle mass (LSMM), which may cause greater treatment toxicities, reduced response to cancer therapy, prolonged hospitalization, impaired quality of life, and worse prognosis.
Methods
This is a retrospective study on advanced PC patients treated at the Department of Oncology of Udine, Italy, from January 2012 to November 2017. Among 162 patients who received chemotherapy, 94 consecutive patients with an available computed tomography (CT) scan were retrospectively analyzed. The primary objective of our study was to explore if an early LSMM ≥ 10% (measured at first radiological evaluation and compared with baseline) and/or baseline sarcopenia may impact prognosis. Baseline sarcopenia was defined according to Prado's criteria. Skeletal muscle area was measured as cross‐sectional areas (cm2) using CT scan data through the Picture archiving and communication system (PACS) image system.
Results
In the whole cohort, 48% of patients were ≤70 years old, and 50% had metastatic disease.
At baseline, 73% of patients had sarcopenia, and 16% presented a visceral fat area ≥ 44 cm2/m2. Overall, 21% experienced an early LSMM ≥ 10%. Approximately 33% of sarcopenic patients at baseline and ~35% of patients with early LSMM ≥ 10% had a body mass index > 25 kg/m2. Of note, 71% of patients were evaluated by a nutritionist, and 56% received a dietary supplementation (oral and/or parenteral). After a median follow‐up of 30.44 months, median overall survival (OS) was 11.28 months, whereas median progression‐free survival (PFS) was 5.72 months. By multivariate analysis, early LSMM ≥ 10% was significantly associated with worse OS [hazard ratio (HR): 2.16; 95% confidence interval (CI) 1.23–3.78; P = 0.007] and PFS (HR: 2.31; 95% CI 1.30–4.09; P = 0.004). Moreover, an exploratory analysis showed that inflammatory indexes, such as neutrophil–lymphocyte ratio variation, impact early LSMM ≥ 10% (odds ratio 1.31, 95% CI 1.06–1.61, P = 0.010).
Conclusions
Early LSMM ≥ 10% has a negative prognostic role in advanced PC patients. Further prospective investigations are needed to confirm these preliminary data.

Basile, D., Parnofiello, A., Vitale, M. G., Cortiula, F., Gerratana, L., Fanotto, V., Lisanti, C., Pelizzari, G., Ongaro, E., Bartoletti, M., Garattini, S. K., Andreotti, V. J., Bacco, A., Iacono, D., Bonotto, M., Casagrande, M., Ermacora, P., Puglisi, F., Pella, N., Fasola, G., Aprile, G., and Cardellino, G. G. (2019) The IMPACT study: early loss of skeletal muscle mass in advanced pancreatic cancer patients. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12368.

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     Article first published online:  01 February 2019

Bumsoo Ahn, Rojina Ranjit, Pavithra Premkumar, Gavin Pharaoh, Katarzyna M. Piekarz, Satoshi Matsuzaki, Dennis R. Claflin, Kaitlyn Riddle, Jennifer Judge, Shylesh Bhaskaran, Kavithalakshmi Satara Natarajan, Erika Barboza, Benjamin Wronowski, Michael Kinter, Kenneth M. Humphries, Timothy M. Griffin, Willard M. Freeman, Arlan Richardson, Susan V. Brooks. Holly Van Remmen

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching
Background
Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated.
Methods
We generated mice lacking skeletal muscle‐specific manganese‐superoxide dismutase (mSod2KO) to increase mtROS using a cre‐Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction.
Results
The mSod2KO mice, contrary to our prediction, exhibit a 10–15% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres (P < 0.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, in situ sciatic nerve‐stimulated isometric maximum‐specific force (N/cm2), force per cross‐sectional area, is impaired by ~60% and associated with increased NMJ fragmentation and size by ~40% (P < 0.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by ~100%, oxidized glutathione is elevated by ~50%, and oxidative modifications of myofibrillar proteins are increased by ~30% (P < 0.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex‐II‐mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (~10 min vs. ~2 h in wild type, P < 0.05).
Conclusions
Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching.

Ahn, B., Ranjit, R., Premkumar, P., Pharaoh, G., Piekarz, K. M., Matsuzaki, S., Claflin, D. R., Riddle, K., Judge, J., Bhaskaran, S., Satara Natarajan, K., Barboza, E., Wronowski, B., Kinter, M., Humphries, K. M., Griffin, T. M., Freeman, W. M., Richardson, A., Brooks, S. V., and Van Remmen, H. (2019) Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12375.

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     Article first published online:  30 January 2019

Jian‐Zi Lin, Jin‐Jian Liang, Jian‐Da Ma, Qian‐Hua Li, Ying‐Qian Mo, Wan‐Mei Cheng, Xiao‐Ling He, Nan Li, Ming‐Hui Cao, Dan Xu, Lie Dai

Myopenia is associated with joint damage in rheumatoid arthritis: a cross‐sectional study
Background
The link between body mass index (BMI) and disease characteristics in rheumatoid arthritis (RA) remains controversial. Body composition (BC) has been more frequently recommended to be used instead of BMI for more accurate assessment. Our study aimed to investigate the characteristics of BC in RA patients and their associations with disease characteristics.
Methods
Body composition was assessed in consecutive Chinese RA patients and control subjects by bioelectric impedance analysis. Overfat was defined by body fat percentage (BF%) as ≥25% for men and ≥35% for women. Myopenia was defined by appendicular skeletal muscle mass index (ASMI) ≤7.0 kg/m2 in men and ≤5.7 kg/m2 in women. BMI and clinical data including disease activity, function, and radiographic assessment were collected. Active disease was defined by disease activity score in 28 joints with four variables including C‐reactive protein (DAS28‐CRP) ≥2.6. Functional limitation was defined as Stanford health assessment questionnaire disability index (HAQ‐DI) >1. Radiographic joint damage (RJD) was defined as the Sharp/van der Heijde modified sharp score (mTSS) >10.
Results
There were 457 RA patients (mean age 49.5 ± 13.1 years old with 82.7% women) and 1860 control subjects (mean age 34.3 ± 9.9 years old with 51.2% women) recruited. Comparisons of BMI and BC between RA patients and control subjects in age and gender stratification showed that lower BMI with 17.7% underweight and lower ASMI with 45.1% myopenia are the main characteristics in RA patients. Compared with those without myopenia, RA patients with myopenia had significantly higher DAS28‐CRP (median 3.5 vs. 3.0), higher HAQ‐DI (median 0.38 vs. 0.13) with higher rate of functional limitation (24.8% vs. 7.6%), and higher mTSS (median 22.3 vs. 9.0) with more RJD (71.8% vs. 45.8%) (all P < 0.001). Multivariate logistic regression analysis showed myopenia were positively associated with functional limitation (OR = 2.546, 95% CI: 1.043–6.217) and RJD (OR = 2.660, 95% CI: 1.443–4.904). All RA patients were divided into four BC subgroups according to overfat and myopenia. Those with both overfat and myopenia had the worst disease characteristics. After adjustment for confounding factors, significant additive interactions were observed between overfat and myopenia in active disease (AP = 0.528, 95% CI: 0.086–0.971), functional limitation (AP = 0.647, 95% CI: 0.356–0.937), and RJD (AP = 0.514, 95% CI: 0.139–0.890).
Conclusions
Myopenia is very common in RA patients that is associated with functional limitation and joint damage in RA. Further research on the underlying mechanism and the effect of skeletal muscle mass improvement in RA management are worth exploring in the future.

Lin, J.‐Z., Liang, J.‐J., Ma, J.‐D., Li, Q.‐H., Mo, Y.‐Q., Cheng, W.‐M., He, X.‐L., Li, N., Cao, M.‐H., Xu, D., and Dai, L. (2019) Myopenia is associated with joint damage in rheumatoid arthritis: a cross‐sectional study. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12381.

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     Article first published online:  30 January 2019

Zhenhui Li, Bolin Cai, Bahareldin Ali Abdalla, Xuenong Zhu, Ming Zheng, Peigong Han, Qinghua Nie, Xiquan Zhang

LncIRS1 controls muscle atrophy via sponging miR‐15 family to activate IGF1‐PI3K/AKT pathway
Background
Recent studies indicate important roles for long noncoding RNAs (lncRNAs) in the regulation of gene expression by acting as competing endogenous RNAs (ceRNAs). However, the specific role of lncRNAs in skeletal muscle atrophy is still unclear. Our study aimed to identify the function of lncRNAs that control skeletal muscle myogenesis and atrophy.
Methods
RNA sequencing was performed to identify the skeletal muscle transcriptome (lncRNA and messenger RNA) between hypertrophic broilers and leaner broilers. To study the ‘sponge’ function of lncRNA, we constructed a lncRNA‐microRNA (miRNA)‐gene interaction network by integrated our previous submitted skeletal muscle miRNA sequencing data. The primary myoblast cells and animal model were used to assess the biological function of the lncIRS1 in vitro or in vivo.
Results
We constructed a myogenesis‐associated lncRNA‐miRNA‐gene network and identified a novel ceRNA lncRNA named lncIRS1 that is specifically enriched in skeletal muscle. LncIRS1 could regulate myoblast proliferation and differentiation in vitro, and muscle mass and mean muscle fibre in vivo. LncIRS1 increases gradually during myogenic differentiation. Mechanistically, lncIRS1 acts as a ceRNA for miR‐15a, miR‐15b‐5p, and miR‐15c‐5p to regulate IRS1 expression, which is the downstream of the IGF1 receptor. Overexpression of lncIRS1 not only increased the protein abundance of IRS1 but also promoted phosphorylation level of AKT (p‐AKT) a central component of insulin‐like growth factor‐1 pathway. Furthermore, lncIRS1 regulates the expression of atrophy‐related genes and can rescue muscle atrophy.
Conclusions
The newly identified lncIRS1 acts as a sponge for miR‐15 family to regulate IRS1 expression, resulting in promoting skeletal muscle myogenesis and controlling atrophy.

Li, Z., Cai, B., Abdalla, B. A., Zhu, X., Zheng, M., Han, P., Nie, Q., and Zhang, X. (2019) LncIRS1 controls muscle atrophy via sponging miR‐15 family to activate IGF1‐PI3K/AKT pathway. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12374.

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     Article first published online:  29 January 2019

Julien Aniort, Alexandre Stella, Carole Philipponnet, Anais Poyet, Cécile Polge, Agnès Claustre, Lydie Combaret, Daniel Béchet, Didier Attaix, Stéphane Boisgard, Marc Filaire, Eugénio Rosset, Odile Burlet‐Schiltz, Anne‐Elisabeth Heng, Daniel Taillandier

Muscle wasting in patients with end‐stage renal disease or early‐stage lung cancer: common mechanisms at work
Background
Loss of muscle mass worsens many diseases such as cancer and renal failure, contributes to the frailty syndrome, and is associated with an increased risk of death. Studies conducted on animal models have revealed the preponderant role of muscle proteolysis and in particular the activation of the ubiquitin proteasome system (UPS). Studies conducted in humans remain scarce, especially within renal deficiency. Whether a shared atrophying programme exists independently of the nature of the disease remains to be established. The aim of this work was to identify common modifications at the transcriptomic level or the proteomic level in atrophying skeletal muscles from cancer and renal failure patients.
Methods
Muscle biopsies were performed during scheduled interventions in early‐stage (no treatment and no detectable muscle loss) lung cancer (LC), chronic haemodialysis (HD), or healthy (CT) patients (n = 7 per group; 86% male; 69.6 ± 11.4, 67.9 ± 8.6, and 70.2 ± 7.9 years P > 0.9 for the CT, LC, and HD groups, respectively). Gene expression of members of the UPS, autophagy, and apoptotic systems was measured by quantitative real‐time PCR. A global analysis of the soluble muscle proteome was conducted by shotgun proteomics for investigating the processes altered.
Results
We found an increased expression of several UPS and autophagy‐related enzymes in both LC and HD patients. The E3 ligases MuRF1 (+56 to 78%, P < 0.01), MAFbx (+68 to 84%, P = 0.02), Hdm2 (+37 to 59%, P = 0.02), and MUSA1/Fbxo30 (+47 to 106%, P = 0.01) and the autophagy‐related genes CTPL (+33 to 47%, P = 0.03) and SQSTM1 (+47 to 137%, P < 0.01) were overexpressed. Mass spectrometry identified >1700 proteins, and principal component analysis revealed three differential proteomes that matched to the three groups of patients. Orthogonal partial least square discriminant analysis created a model, which distinguished the muscles of diseased patients (LC or HD) from those of CT subjects. Proteins that most contributed to the model were selected. Functional analysis revealed up to 238 proteins belonging to nine metabolic processes (inflammatory response, proteolysis, cytoskeleton organization, glucose metabolism, muscle contraction, oxidant detoxification, energy metabolism, fatty acid metabolism, and extracellular matrix) involved in and/or altered by the atrophying programme in both LC and HD patients. This was confirmed by a co‐expression network analysis.
Conclusions
We were able to identify highly similar modifications of several metabolic pathways in patients exhibiting diseases with different aetiologies (early‐stage LC vs. long‐term renal failure). This strongly suggests that a common atrophying programme exists independently of the disease in human.

Aniort, J., Stella, A., Philipponnet, C., Poyet, A., Polge, C., Claustre, A., Combaret, L., Béchet, D., Attaix, D., Boisgard, S., Filaire, M., Rosset, E., Burlet‐Schiltz, O., Heng, A.‐E., and Taillandier, D. (2019) Muscle wasting in patients with end‐stage renal disease or early‐stage lung cancer: common mechanisms at work. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12376.

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     Article first published online:  24 January 2019

Fabrizio Pin, Rafael Barreto, Marion E. Couch, Andrea Bonetto, Thomas M. O'Connell

Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism
Background
Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer‐induced and chemotherapy‐induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments.
Methods
The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer‐induced cachexia. In vivo administration of Folfiri (5‐fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy‐induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance‐based and mass spectrometry‐based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling.
Results
The study involved four groups of CD2F1 male mice (n = 4–5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (−3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (−38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (−47% in CC vs. V; P < 0.001) and depletion of liver glucose (−51% in CC vs. V; P < 0.001) and glycogen (−74% in CC vs. V; P < 0.001). The cancer‐induced and chemotherapy‐induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and β‐oxidation pathways. Cancer‐induced cachexia was uniquely characterized by a dramatic elevation in low‐density lipoprotein particles (+6.9‐fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001).
Conclusions
The results of this study demonstrated for the first time that cancer‐induced and chemotherapy‐induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer‐induced and chemotherapy‐induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia.

Pin, F., Barreto, R., Couch, M. E., Bonetto, A., and O'Connell, T. M. (2018) Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12360.

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     Article first published online:  24 January 2019

Nadja Scherbakov, Charlotte Pietrock, Anja Sandek, Nicole Ebner, Miroslava Valentova, Jochen Springer, Joerg C. Schefold, Stephan von Haehling, Stefan D. Anker, Kristina Norman, Karl Georg Haeusler, Wolfram Doehner

Body weight changes and incidence of cachexia after stroke
Background
Body weight loss is a frequent complication after stroke, and its adverse effect on clinical outcome has been shown in several clinical trials. The purpose of this prospective longitudinal single‐centre observational study was to investigate dynamical changes of body composition and body weight after ischemic stroke and an association with functional outcome.
Methods
Sixty‐seven consecutive patients (age 69 ± 11 years, body mass index 27.0 ± 4.1 kg/m2, 42% female patient, mean ± SD) with acute ischemic stroke with mild to moderate neurological deficit (National Institute of Health Stroke Scale median 4, ranged 0–12) were analysed in the acute phase (4 ± 2 days) and at 12 months (389 ± 26 days) follow‐up. Body composition was examined by dual energy X‐ray absorptiometry. Cachexia was defined according to the consensus definition by body weight loss ≥5% within 1 year and additional clinical signs. Lean tissue wasting was considered if a ratio of upper and lower limbs lean mass sum to squared height (kg/m2) was ≤5.45 kg/m2 for female patient and ≤7.25 kg/m2 for male patient.
Results
According to the body weight changes after 12 months, 42 (63%) patients had weight gain or stable weight, 11 (16%) patients had moderate weight loss, and 14 (21%) patients became cachectic. A relative decline of 19% of fat tissue and 6.5% of lean tissue was observed in cachectic patients, while no changes of lean tissue were observed in non‐cachectic patients after 12 months. The modified Rankin Scale was 48% higher (2.1 ± 1.6, P < 0.05), Barthel Index was 22% lower (71 ± 39, P < 0.01), and handgrip strength was 34% lower (21.9 ± 13.0, P < 0.05) in cachectic compared to non‐cachectic patients after 12 months.
The low physical performance if defined by Barthel Index <60 points was linked to the lean tissue wasting (OR 44.8, P < 0.01), presence of cachexia (OR 20.8, P < 0.01), and low body mass index <25 kg/m2 (OR 11.5, P < 0.05). After adjustment for cofounders, lean tissue wasting remained independently associated with the low physical performance at 12 months follow‐up (OR 137.9, P < 0.05).
Conclusions
In this cohort study, every fifth patient with ischemic stroke fulfilled the criteria of cachexia within 12 months after index event. The incidence of cachexia was 21%. Cachectic patients showed the lowest functional and physical capacity.

Scherbakov, N., Pietrock, C., Sandek, A., Ebner, N., Valentova, M., Springer, J., Schefold, J. C., von Haehling, S., Anker, S. D., Norman, K., Haeusler, K. G., and Doehner, W. (2019) Body weight changes and incidence of cachexia after stroke. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12400.

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     Article first published online:  21 January 2019

Xinxia Zhu, Kevin G. Burfeind, Katherine A. Michaelis, Theodore P. Braun, Brennan Olson, Katherine R. Pelz. Terry K. Morgan, Daniel L. Marks

MyD88 signalling is critical in the development of pancreatic cancer cachexia
Background
Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour-induced inflammation is linked to this multifactorial wasting syndrome, but mechanisms and effective treatments remain elusive. Myeloid differentiation factor (MyD88), a key component of the innate immune system, plays a pivotal role in directing the inflammatory response to various insults. In this study, we tested whether MyD88 signalling is essential in the development of pancreatic cancer cachexia using a robust mouse tumour model.
Methods
Sex, age, and body weight-matched wide type (WT) and MyD88 knockout (MyD88 KO) mice were orthotopically or intraperitoneally implanted with a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D/+ P53R172H/+ Pdx-Cre (KPC) mouse. We observed the effects of MyD88 signalling during pancreatic ductal adenocarcinoma progression and the cachexia development through behavioural, histological, molecular, and survival aspects.
Results
Blocking MyD88 signalling greatly ameliorated pancreatic ductal adenocarcinoma-associated anorexia and fatigue, attenuated lean mass loss, reduced muscle catabolism and atrophy, diminished systemic and central nervous system inflammation, and ultimately improved survival. Our data demonstrate that MyD88 signalling plays a critical role in mediating pancreatic cancer-induced inflammation that triggers cachexia development and therefore represents a promising therapeutic target.
Conclusions
MyD88-dependent inflammation is crucial in the pathophysiology of pancreatic cancer progression and contributes to high mortality. Our findings implicate the importance of innate immune signalling pathways in pancreatic cancer cachexia and a novel therapeutic target.

Zhu, X., Burfeind, K. G., Michaelis, K. A., Braun, T. P., Olson, B., Pelz, K. R., Morgan, T. K., and Marks, D. L. (2019) MyD88 signalling is critical in the development of pancreatic cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12377.

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     Article first published online:  21 January 2019

Willemieke P.M. Dijksterhuis, Maarten J. Pruijt, Stephanie O. van der Woude, Remy Klaassen, Sophie A. Kurk, Martijn G.H. van Oijen, Hanneke W.M. van Laarhoven

Association between body composition, survival, and toxicity in advanced esophagogastric cancer patients receiving palliative chemotherapy
Background
Palliative systemic treatment in patients with advanced or metastatic esophagogastric cancer may result in improved overall survival and quality of life but can also lead to considerable toxicity. In various cancer types, severe muscle mass depletion (sarcopenia) and poor muscle strength are associated with decreased survival and increased chemotherapy-related toxicity. The aim of this study is to determine the impact of body composition on survival and chemotherapy toxicity in esophagogastric cancer patients treated with first-line palliative chemotherapy.
Methods
A total of 88 patients with advanced esophagogastric cancer treated with standard first-line palliative systemic therapy consisting of capecitabine and oxaliplatin (CapOx) between January 2010 and February 2017 were included. Skeletal muscle index (SMI), reflecting muscle mass, and skeletal muscle density (SMD), associated with muscle strength, were measured using pre-treatment of all patients and evaluation computed tomography scans after three treatment cycles of 65 patients and were used to determine sarcopenia and sarcopenic obesity (i.e. sarcopenia and body mass index >25 kg/m2). The associations between body composition (SMI, SMD, sarcopenia, and sarcopenic obesity) and survival and toxicity were assessed using univariable and multivariable Cox and logistic regression analyses, respectively.
Results
Of 88 patients, 75% was male, and median age was 63 (interquartile range 56–69) years. The majority of patients had an adenocarcinoma (83%). Before start of treatment, 49% of the patients were sarcopenic, and 20% had sarcopenic obesity. Low SMD was observed in 50% of patients. During three cycles CapOx, SMI significantly decreased, with a median decrease of 4% (interquartile range -8.6–-0.4). Median progression-free and overall survival were 6.9 and 10.1 months. SMI, SMD, sarcopenia, and sarcopenic obesity (both pre-treatment and after three cycles) were neither associated with progression-free nor overall survival. Pre-treatment SMD was independently associated with grade 3–4 toxicity (odds ratio 0.94; 95% confidence interval 0.89–1.00) and sarcopenic obesity with grade 2–4 neuropathy (odds ratio 3.82; 95% confidence interval 1.20–12.18).
Conclusions
Sarcopenia was not associated with survival or treatment-related toxicity in advanced esophagogastric cancer patients treated with CapOx. Pre-treatment sarcopenic obesity was independently associated with the occurrence of grade 2–4 neurotoxicity and skeletal muscle density with grade 3–4 toxicity.

Dijksterhuis, W. P. M., Pruijt, M. J., van der Woude, S. O., Klaassen, R., Kurk, S. A., van Oijen, M. G. H., and van Laarhoven, H. W. M. (2019) Association between body composition, survival, and toxicity in advanced esophagogastric cancer patients receiving palliative chemotherapy. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12371.

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     Article first published online:  18 January 2019

Anita E.M. Kneppers, Roy A.M. Haast, Ramon C.J. Langen, Lex B. Verdijk, Pieter A. Leermakers, Harry R. Gosker, Luc J.C. van Loon, Mitja Lainscak, Annemie M.W.J. Schols

Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis
Background
Pulmonary rehabilitation (PR) is a cornerstone in the management of chronic obstructive pulmonary disease (COPD), targeting skeletal muscle to improve functional performance. However, there is substantial inter-individual variability in the effect of PR on functional performance, which cannot be fully accounted for by generic phenotypic factors. We performed an unbiased integrative analysis of the skeletal muscle molecular responses to PR in COPD patients and comprehensively characterized their baseline pulmonary and physical function, body composition, blood profile, comorbidities, and medication use.
Methods
Musculus vastus lateralis biopsies were obtained from 51 COPD patients (age 64 ± 1 years, sex 73% men, FEV1, 34 (26–41) %pred.) before and after 4 weeks high-intensity supervised in-patient PR. Muscle molecular markers were grouped by network-constrained clustering, and their relative changes in expression values—assessed by qPCR and western blot—were reduced to process scores by principal component analysis. Patients were subsequently clustered based on these process scores. Pre-PR and post-PR functional performance was assessed by incremental cycle ergometry and 6 min walking test (6MWT).
Results
Eight molecular processes were discerned by network-constrained hierarchical clustering of the skeletal muscle molecular rehabilitation responses. Based on the resulting process scores, four clusters of patients were identified by hierarchical cluster analysis. Two major patient clusters differed in PR-induced autophagy (P < 0.001), myogenesis (P = 0.014), glucocorticoid signalling (P < 0.001), and oxidative metabolism regulation (P < 0.001), with Cluster 1 (C1; n = 29) overall displaying a more pronounced change in marker expression than Cluster 2 (C2; n = 16). General baseline characteristics did not differ between clusters. Following PR, both 6 min walking distance (+26.5 ± 8.3 m, P = 0.003) and peak load on the cycle ergometer test (+9.7 ± 1.9 W, P < 0.001) were improved. However, the functional improvement was more pronounced in C1, as a higher percentage of patients exceeded the minimal clinically important difference in peak workload (61 vs. 21%, P = 0.022) and both peak workload and 6 min walking test (52 vs. 8%, P = 0.008) upon PR.
Conclusions
We identified patient groups with distinct skeletal muscle molecular responses to rehabilitation, associated with differences in functional improvements upon PR.

Kneppers, A. E. M., Haast, R. A. M., Langen, R. C. J., Verdijk, L. B., Leermakers, P. A., Gosker, H. R., van Loon, L. J. C., Lainscak, M., and Schols, A. M. W. J. (2019) Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12370.

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     Article first published online:  17 January 2019

Katherine M. Flegal, John P.A. Ioannidis, Wolfram Doehner

Flawed methods and inappropriate conclusions for health policy on overweight and obesity: the Global BMI Mortality Collaboration meta-analysis
Guideline recommendations and health policy decisions rely on evidence from clinical and epidemiological studies. Adequate methodology and appropriate conclusions are essential to support healthcare and health policy decisions. An analysis of body mass index and mortality by the Global BMI Mortality Collaboration (GBMC) concluded that the association of excess body weight with higher mortality was similar worldwide and that overweight and obesity should be combated everywhere. To reach this conclusion, the GBMC used highly selected data, rather than a systematic approach. The GBMC initially chose individual participant data from 239 prospective studies with approximately 10.6 million participants. The GBMC then excluded over 60% of data and over 75% of fatal events by eliminating all cases with any reported disease at baseline or smoking history and all events within the first 5 years of follow-up. After applying these restrictions, the association of overweight with lower mortality was reversed and the association of obesity with higher mortality was increased. Given the major flaws in the selection process, in the adequacy of the data, in the data analysis, and in the interpretation, the GBMC conclusions should be viewed sceptically as a guide to action, either for clinical decisions or for public health in general. The flawed conclusion that overweight is uniformly associated with substantially increased risk of death and thus should be combated in any circumstances may lead not only to unjustified treatment efforts and potential harm in a wide range of clinical conditions but also to a tremendous waste of resources.

Flegal, K. M., Ioannidis, J. P. A., and Doehner, W. (2019) Flawed methods and inappropriate conclusions for health policy on overweight and obesity: the Global BMI Mortality Collaboration meta-analysis. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12378.

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     Article first published online:  13 January 2019

Justin C. Brown, Elizabeth M. Cespedes Feliciano, Bette J. Caan

The evolution of body composition in oncology—epidemiology, clinical trials, and the future of patient care: facts and numbers
There is growing interest from the oncology community to understand how body composition measures can be used to improve the delivery of clinical care for the 18.1 million individuals diagnosed with cancer annually. Methods that distinguish muscle from subcutaneous and visceral adipose tissue, such as computed tomography (CT), may offer new insights of important risk factors and improved prognostication of outcomes over alternative measures such as body mass index. In a meta-analysis of 38 studies, low muscle area assessed from clinically acquired CT was observed in 27.7% of patients with cancer and associated with poorer overall survival [hazard ratio: 1.44, 95% CI: 1.32–1.56]. Therapeutic interventions such as lifestyle and pharmacotherapy that modify all aspects of body composition and reduce the incidence of poor clinical outcomes are needed in patients with cancer. In a meta-analysis of six randomized trials, resistance training exercise increased lean body mass assessed from dual-energy X-ray absorptiometry [mean difference (MD): +1.07 kg, 95% CI: 0.76–1.37; P < 0.001] and walking distance [MD: +143 m, 95% CI: 70–216; P < 0.001] compared with usual care control in patients with non-metastatic cancer. In a meta-analysis of five randomized trials, anamorelin (a ghrelin agonist) significantly increased lean body mass [MD: +1.10 kg, 95% CI: 0.35–1.85; P = 0.004] but did not improve handgrip strength [MD: 0.52 kg, 95% CI: -0.09–1.13; P = 0.09] or overall survival compared with placebo [HR: 0.99, 95% CI: 0.85–1.14; P = 0.84] in patients with advanced or metastatic cancer. Early screening to identify individuals with occult muscle loss, combined with multimodal interventions that include lifestyle therapy with resistance exercise training and dietary supplementation combined with pharmacotherapy, may be necessary to provide a sufficient stimulus to prevent or slow the cascade of tissue wasting. Rapid, cost-efficient, and feasible methods to quantify muscle and adipose tissue distribution are needed if body composition assessment is to be integrated into large-scale clinical workflows. Fully automated analysis of body composition from clinically acquired imaging is one example. The study of body composition is one of the most provocative areas in oncology that offers tremendous promise to help patients with cancer live longer and healthier lives.

Brown, J. C., Cespedes Feliciano, E. M., and Caan, B. J. (2019) The evolution of body composition in oncology—epidemiology, clinical trials, and the future of patient care: facts and numbers. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12379.

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     Article first published online:  30 November 2018

Junting Liu. Yinkun Yan, Bo Xi, Guimin Huang, Jie Mi on behalf of China Child and Adolescent Cardiovascular Health (CCACH) Study Group

Skeletal muscle reference for Chinese children and adolescents
Background
Skeletal muscle as an essential body composition component plays an important role in maintenance of normal growth and development as well as systemic glucose metabolism in children. No nationwide reference data for skeletal muscle mass for Chinese youths are available in China. We aimed to establish the sex-specific and age-specific percentile reference values of skeletal muscle mass for Chinese children and adolescents.
Methods
This study consisted of 10 818 children and adolescents aged 3–17 years in Chinese urban area during 2013–15. Dual-energy X-ray absorptiometry scan was performed to measure whole body muscle mass and appendicular skeletal muscle mass. Lambda-mu-sigma method was used to obtain the sex-specific and age-specific percentile curves of muscle mass indices.
Results
Overall, whole body muscle mass and appendicular skeletal muscle mass indices showed an increasing trend with age for both sexes, with boys vs. girls having higher values of all muscle mass indices. Whole body muscle mass index in boys increased slightly before age 9 years and then increased rapidly until 15 years and slowed down thereafter, while the mean values in girls increased slightly before age 8 years, increased rapidly until 14 years and remained stable thereafter. Appendicular skeletal muscle mass index increased rapidly until age 16 years and then increased slightly for boys; by contrast, for girls, the mean values increased consistently before age 14 years but showed a slightly decreasing trend after that.
Conclusions
This study established sex-specific and age-specific percentile reference values for skeletal muscle mass for Chinese children and adolescents aged 3–17 years. These reference values can be used to evaluate the muscular development in Chinese children and adolescents.

Liu, J., Yan, Y., Xi, B., Huang, G., Mi, J., and on behalf of China Child and Adolescent Cardiovascular Health (CCACH) Study Group (2018) Skeletal muscle reference for Chinese children and adolescents. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12361.

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     Article first published online:  22 November 2018

William A. Cuellar, Leigh Blizzard, Julie A. Hides, Michele L. Callisaya, Graeme Jones, Flavia Cicuttini, Anita E. Wluka, Changhai Ding, Tania M. Winzenberg

Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial
Background
The effect of vitamin D supplementation on postural muscles of the trunk is of particular interest because low 25-hydroxyvitamin D [25(OH) D] levels are associated with decreased postural balance and increased risk of falls. Understanding the role of vitamin D supplementation plays in trunk muscle function of older adults is necessary, as this is a potentially modifiable factor to improve postural muscle function and decrease the risk of falling of older adults. The objective of this randomized controlled trial was to evaluate the effect of 12 months of vitamin D supplementation compared with placebo, on morphology and function of the trunk muscles of adults aged 50 to 79 years with low serum 25(OH) D levels.
Methods
This was a secondary analysis of a randomized, placebo-controlled, and double-blind clinical trial conducted between June 2010 and December 2013 in Tasmania, Australia. The clinical trial was registered with the Australian New Zealand clinical trial registration agency, ClinicalTrials.gov identifier: NCT01176344; Australian New Zealand Clinical Trials Registry: ACTRN 12610000495022. Participants were aged 50–79 years with ongoing symptoms of knee osteoarthritis and with low serum [25(OH) D] (12.5 to 60 nmol/L, 5.2 to 24 ng/mL). Participants were randomly assigned to either monthly 50 000 IU oral vitamin D3 (n = 104) or an identical placebo (n = 113) for 24 months as per clinical trial protocol. The primary outcomes in this pre-specified secondary analysis were between-group differences in change in size of rectus abdominis, transversus abdominis, internal oblique, external oblique, and lumbar multifidus muscles and function (assessed by change in thickness on contraction) of these muscles (excepting rectus abdominis) from baseline to 12 months. Muscle size was assessed using ultrasound imaging.
Results
Of 217 participants (mean age 63 years, 48% women), 186 (85.7%) completed the study. There were no significant between-group differences in change in size or function of the abdominal or multifidus muscles after 12 months of vitamin D supplementation.
Conclusions
A monthly dose of 50 000 IU of vitamin D3 alone for 12 months does not affect the size or ability to contract trunk muscles of independent community-dwelling older adults with symptomatic knee osteoarthritis and low serum 25(OH) D levels regardless of body mass index status or degree of vitamin D deficiency. An effect of vitamin D supplementation on other aspects of trunk muscle function such as strength, power, or physical function cannot be ruled out.

Cuellar, W. A., Blizzard, L., Hides, J. A., Callisaya, M. L., Jones, G., Cicuttini, F., Wluka, A. E., Ding, C., and Winzenberg, T. M. (2018) Vitamin D supplements for trunk muscle morphology in older adults: secondary analysis of a randomized controlled trial. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12364.

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     Article first published online:  21 November 2018

Qing Zhang, Agnès Duplany, Vincent Moncollin, Sandrine Mouradian, Evelyne Goillot, Laetitia Mazelin, Karine Gauthier, Nathalie Streichenberger, Céline Angleraux, Jie Chen, Shuzhe Ding, Laurent Schaeffer, Yann-Gaël Gangloff

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis
Background
The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age-related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown.
Methods
We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle-specific mTOR knockout (mTORmKO) littermates.
Results
In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice (P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% (P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down-regulation of glycogen phosphorylase expression (0.16-fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V.
Conclusions
Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole-body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole-body homeostasis.

Zhang, Q., Duplany, A., Moncollin, V., Mouradian, S., Goillot, E., Mazelin, L., Gauthier, K., Streichenberger, N., Angleraux, C., Chen, J., Ding, S., Schaeffer, L., and Gangloff, Y.-G. (2018) Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12336.

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     Article first published online:  20 November 2018

Ross D. Dolan, Arwa S. Almasaudi, Ly B. Dieu, Paul G. Horgan, Stephen T. McSorley, Donald C. McMillan

The relationship between computed tomography-derived body composition, systemic inflammatory response, and survival in patients undergoing surgery for colorectal cancer
Introduction
Colorectal cancer is the fourth leading cause of cancer mortality in developed countries. There is evidence supporting a disproportionate loss of skeletal muscle as an independent prognostic factor. The importance of the systemic inflammatory response as a unifying mechanism for specific loss of skeletal muscle mass in patients with cancer is increasingly recognized. The aim of the present study was to delineate the relationship between the systemic inflammatory response, skeletal muscle index (SMI), skeletal muscle density (SMD), and overall survival in patients with colorectal cancer.
Materials and methods
The study included 650 patients with primary operable colorectal cancer. Computed tomography scans were used to define the presence of visceral obesity, sarcopenia (low SMI), and myosteatosis (low SMD). Tumour and patient characteristics were recorded. Survival analysis was carried out using univariate and multivariate Cox regression.
Results
A total of 650 patients (354 men and 296 women) were included. The majority of patients were over 65 years of age (64%) and overweight or obese (68%). On univariate survival analysis, age, ASA, TNM stage, modified Glasgow Prognostic Score (mGPS), body mass index, subcutaneous fat index, visceral obesity, SMI, and SMD were significantly associated with overall survival (all P < 0.05). A low SMI and SMD were significantly associated with an elevated mGPS (<0.05). On multivariate analysis, SMI (Martin) [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.04–2.18, P = 0.031], SMD (Xiao) (HR 1.42, 95% CI 0.98–2.05, P = 0.061), and mGPS (HR 1.44, 95% CI 1.15–1.79, P = 0.001) were independently associated with overall survival. SMD but not SMI was significantly associated with ASA (P < 0.001).
Conclusions
This study delineates the relationship between the loss of quantity and quality of skeletal muscle mass, the systemic inflammatory response, and survival in patients with operable colorectal cancer.

Dolan, R. D., Almasaudi, A. S., Dieu, L. B., Horgan, P. G., McSorley, S. T., and McMillan, D. C. (2018) The relationship between computed tomography-derived body composition, systemic inflammatory response, and survival in patients undergoing surgery for colorectal cancer. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12357.

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     Article first published online:  5 November 2018

Maria Papageorgiou, Thozhukat Sathyapalan, Rudolph Schutte

Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women
Background
Despite several muscle mass measures being used in the current definitions of sarcopenia, their usefulness is uncertain because of limited data on their association with health outcomes. The aim of the study was to compare the performance of different muscle mass measures for predicting incident osteoporosis in postmenopausal women.
Methods
This study included data from 149 166 participants (aged 60.3 ± 5.5 years) as part of the UK Biobank cohort. Body composition was assessed using bioelectrical impedance. The muscle mass measures included were total body skeletal muscle mass (SMM) and appendicular SMM (aSMM) divided by height squared (ht2), derived residuals, SMM, SMM adjusted for body mass (SMM/bm × 100), and aSMM normalized for body mass index (aSMM/BMI). Diagnoses of the events were confirmed by primary care physicians and coded according to the World Health Organization's International Classification of Diseases 10th Revision (ICD‐10: M80‐M82).
Results
Over a median follow‐up of 6.75 (5th to 95th percentile interval, 1.53 to 8.37) years, 394 newly diagnosed cases of osteoporosis occurred, with 40 (10.2%) cases being associated with a pathological fracture. SMM/ht2, aSMM/ht2 residual, and SMM were lower in postmenopausal women with osteoporosis compared with women without (all P < 0.0001), while SMM/bm × 100 (P = 0.003), but not aSMM/BMI (P = 0.59), was higher in the osteoporosis group. The unadjusted rates of osteoporosis increased with decreasing quintiles for SMM/ht2, aSMM/ht2, residuals, and SMM (all P trend <0.0001), while the incidence of osteoporosis increased with increasing SMM/bm × 100 (P trend =0.001), but not for aSMM/BMI (P = 0.45). After minimally adjusting for age and after full adjustment, SMM/ht2, aSMM/ht2, and SMM were the only measure that consistently predicted osteoporosis in the total group of postmenopausal women [hazard ratio (HR) 0.65–0.67, all P ≤ 0.0001], in lean women (HR 0.62–0.68; all P ≤ 0.001), and women with increased adiposity (HR 0.64–0.68; all P ≤ 0.01). In fully adjusted models, the changes in the R2 statistic were 13.4%, 11.6%, and 15.3% for the SMM/ht2 (aSMM/ht2), residual, and SMM, but only 4.9% and 1.3% for SMM/bm × 100 and aSMM/BMI.
Conclusions
Muscle mass measures adjusted for height only (SMM/ht2, aSMM/ht2) appear to be better muscle‐relevant risk factors for incident osteoporosis in postmenopausal women, including when stratified into lean participants and participants with increased adiposity.

Papageorgiou, M., Sathyapalan, T., and Schutte, R. (2018) Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12359.

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     Article first published online:  31 October 2018

Huang‐Jen Chen, Ching‐Chia Wang, Ding‐Cheng Chan, Chen‐Yuan Chiu, Rong‐Sen Yang, Shing‐Hwa Liu

Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass
Background
Acrolein is an extremely electrophilic aldehyde. Increased urinary acrolein adducts have been found in type 2 diabetic patients and people with a smoking habit. The increased blood acrolein was shown in patients who received the cancer drug cyclophosphamide. Both diabetes and smoking are risk factors for skeletal muscle wasting or atrophy. Acrolein has been found to induce myotube atrophy in vitro. The in vitro and in vivo effects and mechanisms of acrolein on myogenesis and the in vivo effect of acrolein on muscle wasting still remain unclear.
Methods
C2C12 myoblasts were used to assess the effects of low‐dose acrolein (0.125–1 μM) on myogenesis in vitro. Mice were exposed daily to acrolein in distilled water by oral administration (2.5 and 5 mg/kg) for 4 weeks with or without glycerol‐induced muscle injury to investigate the effects of acrolein on muscle wasting and regeneration.
Results
Non‐cytotoxic‐concentration acrolein dose dependently inhibited myogenic differentiation in myoblasts (myotube formation inhibition: 0.5 and 1 μM, 66.25% and 46.25% control, respectively, n = 4, P < 0.05). The protein expression for myogenesis‐related signalling molecules (myogenin and phosphorylated Akt: 0.5 and 1 μM, 85.15% and 51.52% control and 62.63% and 56.57% control, respectively, n = 4, P < 0.05) and myosin heavy chain (MHC: 0.5 and 1 μM, 63.64% and 52.53% control, n = 4, P < 0.05) were decreased in acrolein‐treated myoblasts. Over‐expression of the constitutively active form of Akt in myoblasts during differentiation prevented the inhibitory effects of acrolein (1 μM) on myogenesis (MHC and myogenin protein expression: acrolein with or without constitutively active Akt, 64.65% and 105.21% control and 69.14% and 102.02% control, respectively, n = 5, P < 0.05). Oral administration of acrolein for 4 weeks reduced muscle weights (5 mg/kg/day: 65.52% control, n = 6, P < 0.05) and cross‐sectional area of myofibers in soleus muscles (5 mg/kg/day: 79.92% control, n = 6, P < 0.05) with an up‐regulation of atrogin‐1 and a down‐regulation of phosphorylated Akt protein expressions. Acrolein retarded soleus muscle regeneration in a glycerol‐induced muscle regeneration mouse model (5 mg/kg/day: 49.29% control, n = 4, P < 0.05). Acrolein exposure reduced muscle endurance during rotarod fatigue performance in mice with or without glycerol‐induced muscle injury (5 mg/kg/day without glycerol: 30.43% control, n = 4, P < 0.05). Accumulation of acrolein protein adducts could be detected in the soleus muscles of acrolein‐treated mice.
Conclusions
Low‐dose acrolein significantly inhibited myogenic differentiation in vitro, which might be through inhibition of Akt signalling. Acrolein induced muscle wasting and retarded muscle regeneration in mice. These results suggest that acrolein may be a risk factor for myogenesis and disease‐related myopathy.

Chen, H.‐J., Wang, C.‐C., Chan, D.‐C., Chiu, C.‐Y., Yang, R.‐S., and Liu, S.‐H. (2018) Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12362.

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     Article first published online:  31 October 2018

David P.J. van Dijk, Matthew Krill, Farshad Farshidfar, Ting Li, Sander S. Rensen, Steven W.M. Olde Damink, Elijah Dixon, Francis R. Sutherland, Chad G. Ball, Vera C. Mazurak, Vickie E. Baracos; Oliver F. Bathe

Host phenotype is associated with reduced survival independent of tumour biology in patients with colorectal liver metastases
Background
Most prognostic scoring systems for colorectal liver metastases (CRLMs) account for factors related to tumour biology. Little is known about the effects of the host phenotype to the tumour. Our objective was to delineate the relationship of systemic inflammation and body composition features [i.e. low skeletal muscle mass (sarcopenia) and low visceral adipose tissue (VAT)], two well‐described host phenotypes in cancer.
Methods
Clinical data and pre‐operative blood samples were collected from 99 patients who underwent resection of CRLM. Pre‐operative computed tomography scans were available for 97 patients; body composition was analysed at the L3 level, stratified for sex and age. Clinicopathological variables, serum C‐reactive protein (CRP), and various body composition variables were evaluated. Overall survival was evaluated as a function of these same variables in multivariate Cox regression analysis.
Results
Skeletal muscle was significantly correlated with VAT (r = 0.46, P < 0.001). Of patients with sarcopenia, 35 (65%) also had low VAT. C‐reactive protein was elevated (≥5 mg/mL) in 42 patients (43.3%). Elevated CRP was more common in patients with sarcopenia (73.8% vs. 51.1%, P = 0.029). The most significant prognostic factors were the coincidence of elevated CRP and adverse body composition features (sarcopenia and/or low VAT; hazard ratio 4.3, 95% confidence interval 1.5–13.0, P = 0.008), as well as Fong clinical prognostic score (hazard ratio 2.9, 95% confidence interval 1.5–5.5, P = 0.002).
Conclusions
Body composition in patients with CRLM is not directly linked to the presence of systemic inflammation. However, when systemic inflammation coincides with sarcopenia and/or low VAT, prognosis is adversely affected, independent of the Fong clinical prognostic score.

van Dijk, D. P. J., Krill, M., Farshidfar, F., Li, T., Rensen, S. S., Olde Damink, S. W. M., Dixon, E., Sutherland, F. R., Ball, C. G., Mazurak, V. C., Baracos, V. E., and Bathe, O. F. (2018) Host phenotype is associated with reduced survival independent of tumour biology in patients with colorectal liver metastases. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12358.

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     Article first published online:  30 October 2018

Roland Veltkamp, Stefan Uhlmann, Marilena Marinescu, Carsten Sticht,Daniel Finke, Norbert Gretz, Herrmann‐Josef Gröne, Hugo A. Katus, Johannes Backs, Lorenz H. Lehmann

Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction
Background
Stroke can lead to cardiac dysfunction in patients, but the mechanisms underlying the interaction between the injured brain and the heart are poorly understood. The objective of the study is to investigate the effects of experimental murine stroke on cardiac function and molecular signalling in the heart.
Methods and results
Mice were subjected to filament‐induced left middle cerebral artery occlusion for 30 or 60 min or sham surgery and underwent repetitive micro‐echocardiography. Left ventricular contractility was reduced early (24–72 h) but not late (2 months) after brain ischaemia. Cardiac dysfunction was accompanied by a release of high‐sensitive cardiac troponin (hsTNT (ng/ml): d1: 7.0 ± 1.0 vs. 25.0 ± 3.2*; d3: 7.3 ± 1.1 vs. 52.2 ± 16.7*; d14: 5.7 ± 0.8 vs. 5.2 ± 0.3; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); reduced heart weight (heart weight/tibia length ratio: d1: 6.9 ± 0.2 vs. 6.4 ± 0.1*; d3: 6.7 ± 0.2 vs. 5.8 ± 0.1*; d14: 6.7 ± 0.2 vs. 6.4 ± 03; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); resulting from cardiomyocyte atrophy (cardiomyocyte size: d1: 12.8% ± 0.002**; d3: 13.5% ± 0.002**; 14d: 6.3% ± 0.003*; 60 min. MCAO vs. sham; mean ± SEM; **p < 0.01; *p < 0.05), accompanied by increased atrogin‐1 and the E3 ubiquitin ligase murf‐1. Net norepinephrine but not synthesis was increased, suggesting a reduced norepinephrine release or an increase of norepinephrine re‐uptake, resulting in a functional denervation. Transcriptome analysis in cardiac tissue identified the transcription factor peroxisome proliferator‐activated receptor gamma as a potential mediator of stroke‐induced transcriptional dysregulation involved in cardiac atrophy.
Conclusions
Stroke induces a complex molecular response in the heart muscle with immediate but transient cardiac atrophy and dysfunction.

Veltkamp, R., Uhlmann, S., Marinescu, M., Sticht, C., Finke, D., Gretz, N., Gröne, H.‐J., Katus, H. A., Backs, J., and Lehmann, L. H. (2018) Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12335.

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     Article first published online:  29 October 2018

Brianna Bourgeois, Bo Fan, Neil Johannsen, Maria Cristina Gonzalez, Bennett K. Ng, Markus J. Sommer, John A. Shepherd, Steven B. Heymsfield

Improved strength prediction combining clinically available measures of skeletal muscle mass and quality
Background
Measures of skeletal muscle function decline at a faster rate with ageing than do indices of skeletal muscle mass. These observations have been attributed to age‐related changes in muscle quality, another functional determinant separate from skeletal muscle mass. This study tested the hypothesis that improved predictions of skeletal muscle strength can be accomplished by combining clinically available measures of skeletal muscle mass and quality.
Methods
The participants included 146 healthy adult (age ≥ 18 years, range 18–77 years; X ± SD 47 ± 17 years and body mass index 16.5–51.8 kg/m2; 27.7 ± 6.2 kg/m2) men (n = 60) and women (n = 86) in whom skeletal muscle mass was estimated as appendicular lean soft tissue (LST) measured by dual‐energy X‐ray absorptiometry and skeletal muscle quality as bioimpedance analysis‐derived phase angle and B‐mode‐evaluated echogenicity of mid‐thigh skeletal muscle. Strength of the right leg and both arms was quantified as knee isokinetic extension and handgrip strength using dynamometers. The statistical significance of adding phase angle or echogenicity to strength prediction multiple regression models that included extremity‐specific LST and other covariates (e.g. age and sex) was evaluated to test the study hypothesis.
Results
Right leg LST mass alone was significantly (P < 0.0001) correlated with isokinetic right leg strength (R2 = 0.57). The addition of segmental phase angle measured in the right leg at 50 kHz increased the R2 of this model to 0.66 (P < 0.0001); other phase angle frequencies (5 and 250 kHz) did not contribute significantly to these models. Results were similar for both right and left arm handgrip strength prediction models. Adding age and sex as model covariates increased the R2 values of these models further (e.g. right leg strength model R2 increased to 0.71), but phase angle continued to remain a significant (all P < 0.01) predictor of extremity strength. Similarly, when predicting isokinetic right leg strength, mid‐thigh skeletal muscle echogenicity added significantly (P < 0.0001) to right leg LST, increasing R2 from 0.57 to 0.64; age was a significant (P < 0.0001) covariate in this model, increasing R2 further to 0.68.
Conclusions
The hypothesis of the current study was confirmed, strongly supporting and extending earlier reports by quantifying the combined independent effects of skeletal muscle mass and quality on lower‐body and upper‐body measures of strength. These observations provide a clinically available method for future research aimed at optimizing sarcopenia and frailty risk prediction models.

Bourgeois, B., Fan, B., Johannsen, N., Gonzalez, M. C., Ng, B. K., Sommer, M. J., Shepherd, J. A., and Heymsfield, S. B. (2018) Improved strength prediction combining clinically available measures of skeletal muscle mass and quality. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12353.

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     Article first published online:  25 October 2018

Daryl P. Fields, Brandon M. Roberts, Alec K. Simon, Andrew R. Judge, David D. Fuller, Gordon S. Mitchell

Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia
Background
Cancer cachexia is an insidious process characterized by muscle atrophy with associated motor deficits, including diaphragm weakness and respiratory insufficiency. Although neuropathology contributes to muscle wasting and motor deficits in many clinical disorders, neural involvement in cachexia‐linked respiratory insufficiency has not been explored.
Methods
We first used whole‐body plethysmography to assess ventilatory responses to hypoxic and hypercapnic chemoreflex activation in mice inoculated with the C26 colon adenocarcinoma cell line. Mice were exposed to a sequence of inspired gas mixtures consisting of (i) air, (ii) hypoxia (11% O2) with normocapnia, (iii) hypercapnia (7% CO2) with normoxia, and (iv) combined hypercapnia with hypoxia (i.e. maximal chemoreflex response). We also tested the respiratory neural network directly by recording inspiratory burst output from ligated phrenic nerves, thereby bypassing influences from changes in diaphragm muscle strength, respiratory mechanics, or compensation through recruitment of accessory motor pools.
Results
Cachectic mice demonstrated a significant attenuation of the hypoxic tidal volume (0.26mL±0.01mL vs 0.30mL±0.01mL; p<0.05), breathing frequency (317±10bpm vs 344±6bpm; p<0.05) and phrenic nerve (29.5±2.6% vs 78.8±11.8%; p<0.05) responses. On the other hand, the much larger hypercapnic tidal volume (0.46±0.01mL vs 0.46±0.01mL; p>0.05), breathing frequency (392±5bpm vs 408±5bpm; p>0.05) and phrenic nerve (93.1±8.8% vs 111.1±13.2%; p>0.05) responses were not affected. Further, the concurrent hypercapnia/hypoxia tidal volume (0.45±0.01mL vs 0.45±0.01mL; p>0.05), breathing frequency (395±7bpm vs 400±3bpm; p>0.05), and phrenic nerve (106.8±7.1% vs 147.5±38.8%; p>0.05) responses were not different between C26 cachectic and control mice.
Conclusions
Breathing deficits associated with cancer cachexia are specific to the hypoxic ventilatory response and, thus, reflect disruptions in the hypoxic chemoafferent neural network. Diagnostic techniques that detect decompensation and therapeutic approaches that support the failing hypoxic respiratory response may benefit patients at risk for cancer cachectic‐associated respiratory failure.

Fields, D. P., Roberts, B. M., Simon, A. K., Judge, A. R., Fuller, D. D., and Mitchell, G. S. (2018) Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12348.

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     Article first published online:  18 October 2018

Tateaki Naito Shuichi Mitsunaga Satoru Miura Noriatsu Tatematsu Toshimi Inano Takako Mouri Tetsuya Tsuji Takashi Higashiguchi Akio Inui Taro Okayama Teiko Yamaguchi Ayumu Morikawa Naoharu Mori Toshiaki Takahashi Florian Strasser Katsuhiro Omae Keita Mori Koichi Takayama

Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non‐small‐cell lung cancer
Background
Combinations of exercise and nutritional interventions might improve the functional prognosis for cachectic cancer patients. However, high attrition and poor compliance with interventions limit their efficacy. We aimed to test the feasibility of the early induction of new multimodal interventions specific for elderly patients with advanced cancer Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) programme.
Methods
This was a multicentre prospective single‐arm study. We recruited 30 of 46 screened patients aged ≥70 years scheduled to receive first‐line chemotherapy for newly diagnosed, advanced pancreatic, or non‐small‐cell lung cancer. Physical activity was measured using pedometers/accelerometer (Lifecorder®, Suzuken Co., Ltd., Japan). An 8 week educational intervention comprised three exercise and three nutritional sessions. The exercise interventions combined home‐based low‐intensity resistance training and counselling to promote physical activity. Nutritional interventions included standard nutritional counselling and instruction on how to manage symptoms that interfere with patient's appetite and oral intake. Supplements rich in branched‐chain amino acids (Inner Power®, Otsuka Pharmaceutical Co., Ltd., Japan) were provided. The primary endpoint of the study was feasibility, which was defined as the proportion of patients attending ≥4 of six sessions. Secondary endpoints included compliance and safety.
Results
The median patient age was 75 years (range, 70–84). Twelve patients (40%) were cachectic at baseline. Twenty‐nine patients attended ≥4 of the six planned sessions (96.7%, 95% confidence interval, 83.3 to 99.4). One patient dropped out due to deteriorating health status. The median proportion of days of compliance with supplement consumption and exercise performance were 99% and 91%, respectively. Adverse events possibly related to the NEXTAC programme were observed in five patients and included muscle pain (Grade 1 in two patients), arthralgia (Grade 1 in one patient), dyspnoea on exertion (Grade 1 in one patient), and plantar aponeurositis (Grade 1 in one patient).
Conclusions
The early induction of multimodal interventions showed excellent compliance and safety in elderly patients with newly diagnosed pancreatic and non‐small‐cell lung cancer receiving concurrent chemotherapy. We are now conducting a randomized phase II study to measure the impact of these interventions on functional prognosis.

Naito, T., Mitsunaga, S., Miura, S., Tatematsu, N., Inano, T., Mouri, T., Tsuji, T., Higashiguchi, T., Inui, A., Okayama, T., Yamaguchi, T., Morikawa, A., Mori, N., Takahashi, T., Strasser, F., Omae, K., Mori, K., and Takayama, K. (2018) Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non‐small‐cell lung cancer. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12351.

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     Article first published online:  4 October 2018

Maria Conte, Andrea Armani, Giuseppe Conte, Andrea Serra, Claudio Franceschi, Marcello Mele, Marco Sandri, Stefano Salvioli

Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy
Background
Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments.
Methods
By mean of in vivo Plin2 down-regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery.
Results
We found that Plin2 down-regulation was sufficient to induce a 30% increase of myofiber cross-sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients.
Conclusions
Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition.

Conte, M., Armani, A., Conte, G., Serra, A., Franceschi, C., Mele, M., Sandri, M., and Salvioli, S. (2018) Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy. Journal of Cachexia, Sarcopenia and Muscle, https://doi.org/10.1002/jcsm.12355.

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