Article first published online:  10 December 2019

Markus S. Anker, Stefan D. Anker, Andrew J.S. Coats, Stephan von Haehling

The Journal of Cachexia, Sarcopenia and Muscle stays the front‐runner in geriatrics and gerontology
A new syndrome called the ‘motoric–cognitive risk’ (MCR) syndrome has recently been proposed in older persons. According to this definition, the parallel impairment in muscle and brain function is more predictive for identifying subjects at risk of dementia than impairment a in single system alone. Epidemiological studies suggest that among older persons, enrolled in worldwide population‐based studies, 10% are affected by this syndrome, which confers a higher risk of future disability. In detail, the prevalence of MCR in Europe is around 8.0%, 7.0% in the United States, and 6.3% in Japan. The incidence of the MCR syndrome is estimated to be 65.2 per 1000 person years in adults aged 60 years or older. Many studies reported negative outcomes of the syndrome in older persons, emphasizing its clinical impact. In particular, in almost all longitudinal studies, MCR produces a three‐time increased risk of future dementia. In Europe, data from the InCHIANTI study report an increased risk of 2.74 [1.54–4.86], which is 2.49 [1.52–4.10] in the United States and 3.27 [1.55–6.90] in Japan. The studies in different continents are also consistent in showing an increased risk of all‐cause mortality, which is 1.50–1.87 in the Europeans and 1.69 [1.08–2.02] for incident disability in Japan. For the identification of the MCR syndrome, different tests and procedures have been proposed, with a final ‘core‐battery’ that includes gait speed, dual‐task gait speed, the Montreal Cognitive Assessment and Trail Making Test A and B. The criteria used to select this core‐battery were based on the best accuracy for identifying older persons at risk of negative outcomes such as dementia, falls, aging‐related disabilities, and sensitivity to interventions. The selection of these tests will allow to start studies aimed to better capture older persons at higher risk of mobility and cognitive disability. By these tests, it will be possible to better evaluate the effect of treatment composing of tailored physical exercise, nutritional suggestions, and medical therapy to overturn negative effect of both cognitive and motoric frailty. This article provides an overview of the current knowledge of the MCR syndrome.

MAnker, M. S., Anker, S. D., Coats, A. J. S., and von Haehling, S. ( 2019) The Journal of Cachexia, Sarcopenia and Muscle stays the front‐runner in geriatrics and gerontology, Journal of Cachexia, Sarcopenia and Muscle, 10, 1151– 1164. https://doi.org/10.1002/jcsm.12518.

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     Article first published online:  07 August 2019

Jorne Ubachs, Janine Ziemons, Iris J.G. Minis‐Rutten, Roy F.P.M. Kruitwagen, Jos Kleijnen, Sandrina Lambrechts, Steven W.M. Olde Damink, Sander S. Rensen, Toon Van Gorp

Sarcopenia and ovarian cancer survival: a systematic review and meta‐analysis

Background
Sarcopenia is the loss of skeletal muscle mass and function that occurs with advancing age and certain diseases. It is thought to have a negative impact on survival in cancer patients. Routine computed tomography imaging is often used to quantify skeletal muscle in cancer patients. Sarcopenia is defined by a low skeletal muscle index (SMI). Skeletal muscle radiation attenuation (SMRA) is used to define muscle quality. The primary aim of this meta‐analysis was to study the association between sarcopenia or SMRA and overall survival (OS) or complications in patients with ovarian cancer.
Methods
Medline, Embase, CINAHL, and PEDro databases were searched from inception to 15 February 2019. Studies evaluating the prognostic effect of SMI and SMRA on ovarian cancer survival or surgical complications were included. Risk of bias and study quality were evaluated with the Quality in Prognosis Studies Instrument (QUIPS) according to the modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.
Results
The search strategy yielded 4262 hits in all four databases combined. Ten and eight studies were included for qualitative and quantitative analysis, respectively. Meta‐analysis revealed a significant association between the SMI and OS [0.007; hazard ratio (HR): 1.11, 95% confidence interval (CI): 1.03–1.20]. SMRA was also significantly associated with OS (P < 0.001; HR: 1.14, 95% CI: 1.08–1.20). Association between the SMI and surgical complications had borderline statistical significance (0.05; HR: 1.23, 95% CI: 1.00–1.52). The risk of bias assessed with QUIPS was high in all studies. The quality of the evidence was very low.
Conclusions
Whereas our meta‐analysis indicated that a low SMI and low SMRA are associated with survival in ovarian cancer patients, the low quality of the source data precludes drawing definitive conclusions.

Ubachs, J., Ziemons, J., Minis‐Rutten, I. J. G., Kruitwagen, R. F. P. M., Kleijnen, J., Lambrechts, S., Olde Damink, S. W. M., Rensen, S. S., and Van Gorp, T. ( 2019) Sarcopenia and ovarian cancer survival: a systematic review and meta‐analysis, Journal of Cachexia, Sarcopenia and Muscle, 10, 1165– 1174. https://doi.org/10.1002/jcsm.12468.

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     Article first published online:  20 August 2019

Jennifer G. Le‐Rademacher, Elizabeth M. Storrick, Aminah Jatoi

Remarks on the design and analyses of longitudinal studies for cancer patients with anorexia and weight loss

Longitudinal data serve an important role in understanding the cancer anorexia weight loss syndrome and in testing interventions to palliative and treat patients who develop this syndrome. The element of time and the interrelatedness of data points define longitudinal data and add to the richness of this type of data. However, longitudinal data can also give rise to non‐random, missing data that can lead to flawed conclusions. This paper discusses these issues and suggests practical considerations for design and analysis of longitudinal cancer anorexia weight loss studies.

ULe‐Rademacher, J. G., Storrick, E. M., and Jatoi, A. ( 2019) Remarks on the design and analyses of longitudinal studies for cancer patients with anorexia and weight loss, Journal of Cachexia, Sarcopenia and Muscle, 10, 1175– 1182. https://doi.org/10.1002/jcsm.12480.

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     Article first published online:  22 August 2019

Rebeka Tomasin, Ana Carolina Baptista Moreno Martin, Márcia Regina Cominetti

Metastasis and cachexia: alongside in clinics, but not so in animal models

Cancer cachexia is a paraneoplastic syndrome characterized by lean mass wasting (with or without fat mass decrease), culminating in involuntary weight loss, which is the key clinical observation nowadays. There is a notable lack of studies involving animal models to mimic the clinical reality, which are mostly patients with cachexia and metastatic disease. This mismatch between the clinical reality and animal models could at least partly contribute to the poor translation observed in the field. In this paper, we retrieved and compared animal models used for cachexia research from 2017 and 10 years earlier (2007) and observed that very little has changed. Especially, clinically relevant models where cachexia is studied in an orthotopic or metastatic context were and still are very scarce. Finally, we described and supported the biological rationale behind why, despite technical challenges, these two phenomena—metastasis and cachexia—should be modelled in parallel, highlighting the overlapping pathways between them. To sum up, this review aims to contribute to rethinking and possibly switching the models currently used for cachexia research, to hopefully obtain better and more translational outcomes.

Tomasin, R., Martin, A. C. B. M., and Cominetti, M. R. ( 2019) Metastasis and cachexia: alongside in clinics, but not so in animal models, Journal of Cachexia, Sarcopenia and Muscle, 10, 1183– 1194. https://doi.org/10.1002/jcsm.12475.

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     Article first published online:  16 July 2019

Benjamin F. Miller,Leslie M. Baehr, Robert V. Musci, Justin J. Reid, Frederick F. Peelor III, Karyn L. Hamilton, Sue C. Bodine

Muscle‐specific changes in protein synthesis with aging and reloading after disuse atrophy

Background
Successful strategies to halt or reverse sarcopenia require a basic understanding of the factors that cause muscle loss with age. Acute periods of muscle loss in older individuals have an incomplete recovery of muscle mass and strength, thus accelerating sarcopenic progression. The purpose of the current study was to further understand the mechanisms underlying the failure of old animals to completely recover muscle mass and function after a period of hindlimb unloading.
Methods
Hindlimb unloading was used to induce muscle atrophy in Fischer 344–Brown Norway (F344BN F1) rats at 24, 28, and 30 months of age. Rats were hindlimb unloaded for 14 days and then reloaded at 24 months (Reloaded 24), 28 months (Reloaded 28), and 24 and 28 months (Reloaded 24/28) of age. Isometric torque was determined at 24 months of age (24 months), at 28 months of age (28 months), immediately after 14 days of reloading, and at 30 months of age (30 months). During control or reloaded conditions, rats were labelled with deuterium oxide (D2O) to determine rates of muscle protein synthesis and RNA synthesis.
Results
After 14 days of reloading, in vivo isometric torque returned to baseline in Reloaded 24, but not Reloaded 28 and Reloaded 24/28. Despite the failure of Reloaded 28 and Reloaded 24/28 to regain peak force, all groups were equally depressed in peak force generation at 30 months. Increased age did not decrease muscle protein synthesis rates, and in fact, increased resting rates of protein synthesis were measured in the myofibrillar fraction (Fractional synthesis rate (FSR): %/day) of the plantaris (24 months: 2.53 ± 0.17; 30 months: 3.29 ± 0.17), and in the myofibrillar (24 months: 2.29 ± 0.07; 30 months: 3.34 ± 0.11), collagen (24 months: 1.11 ± 0.07; 30 months: 1.55 ± 0.14), and mitochondrial (24 months: 2.38 ± 0.16; 30 months: 3.20 ± 0.10) fractions of the tibialis anterior (TA). All muscles increased myofibrillar protein synthesis (%/day) in Reloaded 24 (soleus: 3.36 ± 0.11, 5.23 ± 0.19; plantaris: 2.53 ± 0.17, 3.66 ± 0.07; TA: 2.29 ± 0.14, 3.15 ± 0.12); however, in Reloaded 28, only the soleus had myofibrillar protein synthesis rates (%/day) >28 months (28 months: 3.80 ± 0.10; Reloaded 28: 4.86 ± 0.19). Across the muscles, rates of protein synthesis were correlated with RNA synthesis (all muscles combined, R2 = 0.807, P < 0.0001).
Conclusions
These data add to the growing body of literature that indicate that changes with age, including following disuse atrophy, differ by muscle. In addition, our findings lead to additional questions of the underlying mechanisms by which some muscles are maintained with age while others are not.

Miller, B. F., Baehr, L. M., Musci, R. V., Reid, J. J., Peelor, F. F., Hamilton, K. L., and Bodine, S. C. ( 2019) Muscle‐specific changes in protein synthesis with aging and reloading after disuse atrophy, Journal of Cachexia, Sarcopenia and Muscle, 10, 1195– 1209. https://doi.org/10.1002/jcsm.12470.

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     Article first published online:  11 September 2019

Jiao Wu, Jiangling Dong, Daniela Verzola, Keith Hruska, Giacomo Garibotto, Zhaoyong Hu, William E. Mitch, Sandhya S. Thomas

Signal regulatory protein alpha initiates cachexia through muscle to adipose tissue crosstalk

Background
Muscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRPα), which leads to cachexia in mice and is associated with cachexia in patients with CKD.
Methods
We assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRPα and sought mediators of metabolic responses in muscle and adipose tissues of mice with either muscle‐specific or adipose tissue‐specific KO of SIRPα. Metabolic responses were confirmed in primary cultures of adipose cells.
Results
In mice with CKD, SIRPα expression was increased in WAT (three‐fold, P < 0.05), and this was associated with precursors of cachexia: ‘pathologic browning', thermogenesis, and a two‐fold activation of protein kinase A (P < 0.05 vs. control mice) plus loss of adipose tissue mass. In contrast, mice with SIRPα global KO and CKD or acute diabetes experienced improved insulin signalling and activation of pAkt plus ‘physiologic browning' of WAT. These mice avoided losses of muscle and adipose tissues and experienced a 31% improvement in survival (P < 0.05) than did wild‐type mice with CKD. In muscle‐specific SIRPα KO mice with CKD, we uncovered that serum SIRPα levels (P < 0.05) were suppressed and were associated with improved insulin signalling both in skeletal muscles and in WAT. These changes were accompanied by physiologic WAT browning. However, in adipose‐specific SIRPα KO mice with CKD, levels of serum SIRPα were increased over two‐fold (P < 0.05), while muscle losses were minimally inhibited. Clinical implications of SIRPα signalling are suggested by our findings that include increased SIRPα expression in muscle and adipose tissues (P < 0.05 vs. healthy controls) plus higher SIRPα levels in the serum of patients with CKD (2.4‐fold, P=0.000017 vs. healthy controls).
Conclusions
Our results show that SIRPα plays an important role as an anti‐insulin mediator regulating pathways to cachexia. In muscle‐specific SIRPα KO, changes in SIRPα serum levels seem to improve insulin signalling in muscle and WAT, suggesting crosstalk between muscle and adipose tissue. Therefore, targeting SIRPα may prevent cachexia in patients with CKD or acute diabetes.

Wu, J., Dong, J., Verzola, D., Hruska, K., Garibotto, G., Hu, Z., Mitch, W. E., and Thomas, S. S. ( 2019) Signal regulatory protein alpha initiates cachexia through muscle to adipose tissue crosstalk, Journal of Cachexia, Sarcopenia and Muscle, 10, 1210– 1227. https://doi.org/10.1002/jcsm.12459.

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     Article first published online:  21 June 2019

Christian M. Girgis, Kuan Minn Cha, Benjamin So, Michael Tsang, Jennifer Chen, Peter J. Houweling, Aaron Schindeler, Rebecca Stokes, Michael M. Swarbrick, Frances J. Evesson,  Sandra T. Cooper, Jenny E. Gunton

Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function

Background
It has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte‐specific deletion of VDR would provide a strategy to answer this question.
Methods
Myocyte‐specific vitamin D receptor (mVDR) null mice were generated by crossing human skeletal actin‐Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real‐time PCR.
Results
Unlike whole‐body VDR knockout mice, mVDR mice showed a normal body size. The mVDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel‐running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7–16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, mVDR have increased proportional fat mass at 20% compared with 13%.
Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1, D2, and D3 and cyclin‐dependent kinases Cdk‐2 and Cdk‐4. Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin mRNA was lower in mVDR muscle.
Conclusions
This study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size.

Girgis, C. M., Cha, K. M., So, B., Tsang, M., Chen, J., Houweling, P. J., Schindeler, A., Stokes, R., Swarbrick, M. M., Evesson, F. J., Cooper, S. T., and Gunton, J. E. ( 2019) Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function, Journal of Cachexia, Sarcopenia and Muscle, 10, 1228– 1240. https://doi.org/10.1002/jcsm.12460.

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     Article first published online:  11 August 2019

Xiuqing Han, Lisbeth Liliendal Valbjørn Møller, Estelle De Groote, Kirstine Nyvold Bojsen‐Møller, Jonathan Davey, Carlos Henríquez‐Olguin, Zhencheng Li, Jonas Roland Knudsen, Thomas Elbenhardt Jensen, Sten Madsbad, Paul Gregorevic, Erik Arne Richter, Lykke Sylow

Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle

Background
Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF‐β) superfamily, including activin A, which causes atrophy. TGF‐β superfamily ligands also negatively regulate insulin‐sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.
Methods
To elucidate if TGF‐β superfamily ligands regulate insulin action, we used an adeno‐associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet‐induced obese mice. We determined basal and insulin‐stimulated 2‐deoxy‐glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux‐en‐Y gastric bypass (RYGB).
Results
Fst288 muscle overexpression markedly increased in vivo insulin‐stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase‐E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin‐stimulated protein synthesis, but no correlation was observed between the Fst288‐driven hypertrophy and the increase in insulin‐stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin‐resistant diet‐induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (−24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.
Conclusions
We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase‐E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post‐RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF‐β superfamily ligands to improve insulin action and Fst's relevance to muscle wasting‐associated insulin‐resistant conditions in mice and humans.

Han, X., Møller, L. L. V., De Groote, E., Bojsen‐Møller, K. N., Davey, J., Henríquez‐Olguin, C., Li, Z., Knudsen, J. R., Jensen, T. E., Madsbad, S., Gregorevic, P., Richter, E. A., and Sylow, L. ( 2019) Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle, Journal of Cachexia, Sarcopenia and Muscle, 10, 1241– 1257. https://doi.org/10.1002/jcsm.12474.

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     Article first published online:  30 October 2019

Mauro Monforte, Francesco Laschena, Pierfrancesco Ottaviani, Maria Rosaria Bagnato, Anna Pichiecchio, Giorgio Tasca, Enzo Ricci

Tracking muscle wasting and disease activity in facioscapulohumeral muscular dystrophy by qualitative longitudinal imaging

Background
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent late‐onset muscular dystrophies, characterized by progressive fatty replacement and degeneration involving single muscles in an asynchronous manner. With clinical trials at the horizon in this disease, the knowledge of its natural history is of paramount importance to understand the impact of new therapies. The aim of this study was to assess disease progression in FSHD using qualitative muscle magnetic resonance imaging, with a focus on the evolution of hyperintense lesions identified on short‐tau inversion recovery (STIR+) sequences, hypothesized to be markers of active muscle injury.
Methods
One hundred genetically confirmed consecutive FSHD patients underwent lower limb muscle magnetic resonance imaging at baseline and after 365 ± 60 days in this prospective longitudinal study. T1 weighted (T1w) and STIR sequences were used to assess fatty replacement using a semiquantitative visual score and muscle oedema. The baseline and follow‐up scans of each patient were also evaluated by unblinded direct comparison to detect the changes not captured by the scoring system.
Results
Forty‐nine patients showed progression on T1w sequences after 1 year, and 30 patients showed at least one new STIR+ lesion. Increased fat deposition at follow‐up was observed in 13.9% STIR+ and in only 0.21% STIR‐ muscles at baseline (P < 0.001). Overall, 89.9% of the muscles that showed increased fatty replacement were STIR+ at baseline and 7.8% were STIR+ at 12 months. A higher number of STIR+ muscles at baseline was associated with radiological worsening (odds ratio 1.17, 95% confidence interval 1.06–1.30, P = 0.003).
Conclusions
Our study confirms that STIR+ lesions represent prognostic biomarkers in FSHD and contributes to delineate its radiological natural history, providing useful information for clinical trial design. Given the peculiar muscle‐by‐muscle involvement in FSHD, MRI represents an invaluable tool to explore the modalities and rate of disease progression.

Monforte, M., Laschena, F., Ottaviani, P., Bagnato, M. R., Pichiecchio, A., Tasca, G., and Ricci, E. ( 2019) Tracking muscle wasting and disease activity in facioscapulohumeral muscular dystrophy by qualitative longitudinal imaging, Journal of Cachexia, Sarcopenia and Muscle, 10, 1258– 1265. https://doi.org/10.1002/jcsm.12473.

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     Article first published online:  13 August 2019

Mikel L. Sáez de Asteasu, Nicolás Martínez‐Velilla, Fabricio Zambom‐Ferraresi, Álvaro Casas‐Herrero, Eduardo L. Cadore, Robinson Ramirez‐Velez, Mikel Izquierdo

Inter‐individual variability in response to exercise intervention or usual care in hospitalized older adults

Background
Exercise protocols applied during hospitalization can prevent functional and cognitive decline in older adults. The purpose of this study was to examine the individual response of acutely hospitalized patients to usual care and to physical exercise on functional capacity, muscle strength, and cognitive function and to assess the relationship with mortality at 1 year post‐discharge.
Methods
In a single‐blind randomized clinical trial, 370 hospitalized patients [56.5% women; mean age (standard deviation) 87.3 (4.9) years] were allocated to an exercise intervention group (IG, n = 185) or a control group (CG, n = 185). The participants were older adults aged 75 years or older in an acute care unit in a tertiary public hospital in Navarra, Spain. The usual care group received habitual hospital care, which included physical rehabilitation when needed. The in‐hospital intervention included individualized multicomponent exercise training programme performed during 5–7 consecutive days (two sessions/day). Functional capacity was assessed with the Short Physical Performance Battery (SPPB) test and the Gait Velocity Test (GVT). Handgrip strength and cognitive function were also measured at admission and discharge. Patients in both groups were categorized as responders (Rs), non‐responders (NRs), and adverse responders (ARs) based on the individual response to each treatment during hospitalization.
Results
The prevalence of Rs was higher and the prevalence of NRs and ARs was lower in the intervention group than in the control group for functional capacity (SPPB IG: Rs 85.3%, NRs 8.7%, ARs 6.0% vs. CG: Rs 37.9%, NRs 28.8%, ARs 33.3% and GVT IG: Rs 51.2%, NRs 47.3, ARs 1.6% vs. CG: Rs 18.0%, NRs 67.7%, ARs 14.3%), muscle strength (IG: Rs 62.3%, NRs 26.5%, ARs 11.3% vs. CG: Rs 20.0%, NRs 38.0%, ARs 42.0%), and cognition (IG: Rs 41.5%, NRs 57.1%, ARs 1.4% vs. CG: Rs 13.8%, NRs 76.6%, ARs 9.7%) (all P < 0.001). The ARs for the GVT in the control group and the ARs for the SPPB in the intervention group had a significantly higher rate of mortality than the NRs and Rs in the equivalent groups (0.01 and 0.03, respectively) at follow‐up.
Conclusions
Older patients performing an individualized exercise intervention presented higher prevalence of Rs and a lower prevalence of NRs and ARs for functional capacity, muscle strength, and cognitive function than those who were treated with usual care during acute hospitalization. An adverse response on functional capacity in older patients to physical exercise or usual care during hospitalization was associated with mortality at 1 year post‐discharge.

Sáez de Asteasu, M. L., Martínez‐Velilla, N., Zambom‐Ferraresi, F., Casas‐Herrero, Á., Cadore, E. L., Ramirez‐Velez, R., and Izquierdo, M. ( 2019) Inter‐individual variability in response to exercise intervention or usual care in hospitalized older adults, Journal of Cachexia, Sarcopenia and Muscle, 10, 1266– 1275. https://doi.org/10.1002/jcsm.12481.

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     Article first published online:  30 September 2019

Nima Gharahdaghi, Supreeth Rudrappa, Matthew S. Brook, Iskandar Idris, Hannah Crossland, Claire Hamrock, Muhammad Hariz Abdul Aziz, Fawzi Kadi, Janelle Tarum, Paul L. Greenhaff, Dumitru Constantin‐Teodosiu, Jessica Cegielski, Bethan E. Phillips, Daniel J. Wilkinson, Nathaniel J. Szewczyk, Kenneth Smith, Philip J. Atherton

Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men

Background
The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia), and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy and physiological and molecular impacts of T therapy adjuvant to short‐term RET remain poorly defined.
Methods
Eighteen non‐hypogonadal healthy older men, 65–75 years, were assigned in a random double‐blinded fashion to receive, biweekly, either placebo (P, saline, n = 9) or T (Sustanon 250 mg, n = 9) injections over 6 week whole‐body RET (three sets of 8–10 repetitions at 80% one‐repetition maximum). Subjects underwent dual‐energy X‐ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic/anabolic gene expression, anabolic signalling, muscle protein synthesis (D2O), and breakdown (extrapolated).
Results
Testosterone adjuvant to RET augmented total fat‐free mass (P=0.007), legs fat‐free mass (P=0.02), and appendicular fat‐free mass (P=0.001) gains while decreasing total fat mass (P=0.02). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross‐section area with RET occured to a greater extent in T (P < 0.05). Sum strength (P=0.0009) and maximal voluntary contract (e.g. knee extension at 70°) (P=0.002) increased significantly more in the T group. Mechanistically, both muscle protein synthesis rates (T: 2.13 ± 0.21%·day−1 vs. P: 1.34 ± 0.13%·day−1, P=0.0009) and absolute breakdown rates (T: 140.2 ± 15.8 g·day−1 vs. P: 90.2 ± 11.7 g·day−1, P=0.02) were elevated with T therapy, which led to higher net turnover and protein accretion in the T group (T: 8.3 ± 1.4 g·day−1 vs. P: 1.9 ± 1.2 g·day−1, P=0.004). Increases in ribosomal biogenesis (RNA:DNA ratio); mRNA expression relating to T metabolism (androgen receptor: 1.4‐fold; Srd5a1: 1.6‐fold; AKR1C3: 2.1‐fold; and HSD17β3: two‐fold); insulin‐like growth factor (IGF)‐1 signalling [IGF‐1Ea (3.5‐fold) and IGF‐1Ec (three‐fold)] and myogenic regulatory factors; and the activity of anabolic signalling (e.g. mTOR, AKT, and RPS6; P < 0.05) were all up‐regulated with T therapy. Only T up‐regulated mitochondrial citrate synthase activity (P=0.03) and transcription factor A (1.41 ± 0.2‐fold, P=0.0002), in addition to peroxisome proliferator‐activated receptor‐γ co‐activator 1‐α mRNA (1.19 ± 0.21‐fold, P=0.037).
Conclusions
Administration of T adjuvant to RET enhanced skeletal muscle mass and performance, while up‐regulating myogenic gene programming, myocellular translational efficiency and capacity, collectively resulting in higher protein turnover, and net protein accretion. T coupled with RET is an effective short‐term intervention to improve muscle mass/function in older non‐hypogonadal men.

Gharahdaghi, N., Rudrappa, S., Brook, M. S., Idris, I., Crossland, H., Hamrock, C., Abdul Aziz, M. H., Kadi, F., Tarum, J., Greenhaff, P. L., Constantin‐Teodosiu, D., Cegielski, J., Phillips, B. E., Wilkinson, D. J., Szewczyk, N. J., Smith, K., and Atherton, P. J. ( 2019) Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men, Journal of Cachexia, Sarcopenia and Muscle, 10, 1276– 1294. https://doi.org/10.1002/jcsm.12472.

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     Article first published online:  11 September 2019

Lingxiao He, Praval Khanal, Christopher I. Morse, Alun Williams, Martine Thomis

Differentially methylated gene patterns between age‐matched sarcopenic and non‐sarcopenic women

Background
Sarcopenia is characterized by progressive decreases in muscle mass, muscle strength, and muscle function with ageing. Although many studies have investigated the mechanisms of sarcopenia, its connection with epigenetic factors, such as DNA methylation, still remains poorly understood. The aim of this study was to explore sarcopenia‐related DNA methylation differences in blood samples between age‐matched sarcopenic and non‐sarcopenic older women.
Methods
A sarcopenic group (n = 24) was identified and selected from a set of 247 older Caucasian women (aged 65–80 years) based on cut‐off points of skeletal muscle index at 6.75 kg/m2 and grip strength at 26 kg (the lower quintile of grip strength in the set). A non‐sarcopenic group (n = 24) was created with a similar age distribution as that of the sarcopenic group. DNA methylation patterns of whole blood samples from both groups were analysed using Infinium MethylationEPIC BeadChip arrays. Differentially methylated cytosin–phosphate–guanine sites (dmCpGs) were identified at a P value threshold of 0.01 by comparing methylation levels between the sarcopenic and non‐sarcopenic groups at each CpG site. dmCpG‐related genes were annotated based on Homo sapiens hg19 genome build. The functions of these genes were further examined by GO and KEGG pathway enrichment analysis.
Results
The global methylation level of all analysed CpG sites (n = 788 074) showed no significant difference between the sarcopenic and non‐sarcopenic groups (0.812), while the average methylation level of dmCpGs (n = 6258) was significantly lower in the sarcopenic group (0.004). The sarcopenic group had significantly higher methylation levels in TSS200 (the region from transcription start site to 200 nucleotides upstream of the site) and lower methylation levels in gene body and 3'UTR regions. In respect of CpG regions, CpG islands in promoters and some intragenic regions showed greater levels of methylation in the sarcopenic group. dmCpG‐related KEGG pathways were mainly associated with muscle function, actin cytoskeleton regulation, and energy metabolism. Seven genes (HSPB1, PBX4, CNKSR3, ORMDL3, MIR10A, ZNF619, and CRADD) were found with the same methylation direction as previous studies of blood sample methylation during ageing. Fifty‐four genes were shared with previous studies of resistance training.
Conclusions
Our results improve understanding of epigenetic mechanisms of sarcopenia by identifying sarcopenia‐related DNA methylation differences in blood samples of older women. These methylation differences suggest underlying alterations of gene expression and pathway function, which can partially explain sarcopenia‐related muscular changes.

He, L., Khanal, P., Morse, C. I., Williams, A., and Thomis, M. ( 2019) Differentially methylated gene patterns between age‐matched sarcopenic and non‐sarcopenic women, Journal of Cachexia, Sarcopenia and Muscle, 10, 1295– 1306. https://doi.org/10.1002/jcsm.12478.

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     Article first published online:  09 August 2019

Jacek T. Niedziela, Bartosz Hudzik, Krzysztof Strojek, Lech Poloński, Mariusz Gąsior, Piotr Rozentryt

Weight loss in heart failure is associated with increased mortality only in non‐obese patients without diabetes

Background
Weight loss (WL) is an independent predictor of mortality in patients with heart failure (HF). Moderate WL is recommended for overweight or obese patients with type 2 diabetes mellitus (DM). The aim of this study was to assess the prognostic impact of body weight reduction on survival in patients with both HF with reduced ejection fraction (HFrEF) and DM.
Methods
The study comprised patients with HFrEF at the outpatient clinic. WL was defined as a body weight reduction of at least 7.5% during at least 6 months. Clinical features and 1 year mortality were analysed in WL and DM groups. Multivariate regression model was chosen to assess the predictive role of WL in HF patients with and without DM. The analysis regarding obesity before HF was also performed.
Results
The study comprised 777 patients with HFrEF. Mean age was 53.2 ± 9.2, 12.0% were women, mean EF was 23.7 ± 6.0 %, and New York Heart Association III or IV class, DM, and WL were found in 60.5%, 33.3%, and 47.1% patients, respectively. WL was more prevalent in diabetic patients, comparing with those without DM (53.7% vs. 43.8%, respectively, 0.01), and was associated with higher 1 year mortality only in non‐diabetic group (17.6% for WL vs. 8.2% for non‐WL, log‐rank 0.001). In the multivariate analysis, WL was associated with a higher risk of 1 year mortality in non‐diabetic patients: HR 1.76 (1.05–2.95), 0.03 and only in the subgroup without obesity: HR 2.35 (1.28–4.32), 0.006. In non‐diabetic patients with obesity and in diabetic patients regardless of weight status, WL was not associated with worse prognosis (thereof, WL was excluded from the multivariate models).
Conclusions
Overall, WL in HFrEF has emerged as a predictor of unfavourable outcomes only in non‐obese patients without DM. More importantly, this study has identified that the presence of DM (irrespective of weight status) or the presence of obesity in non‐diabetic patients abolished the unfavourable impact of WL on long‐term outcomes.

Niedziela, J. T., Hudzik, B., Strojek, K., Poloński, L., Gąsior, M., and Rozentryt, P. ( 2019) Weight loss in heart failure is associated with increased mortality only in non‐obese patients without diabetes, Journal of Cachexia, Sarcopenia and Muscle, 10, 1307– 1315. https://doi.org/10.1002/jcsm.12471.

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     Article first published online:  16 August 2019

Charlotte Suetta, Bryan Haddock, Julian Alcazar, Tim Noerst, Ole M. Hansen, Helle Ludvig, Rikke Stefan Kamper, Peter Schnohr, Eva Prescott, Lars L. Andersen, Ulrik Frandsen, Per Aagaard, Jens Bülow, Peter Hovind, Lene Simonsen

The Copenhagen Sarcopenia Study: lean mass, strength, power, and physical function in a Danish cohort aged 20–93 years

Background
Despite no international consensus on the diagnostic criteria for sarcopenia, low lean mass, muscle strength, and physical function are important risk factors for disability, frailty, and mortality in older individuals, as well as in a wide range of patients with muscle loss. Here, we provide a population‐based reference material of total and regional lean body mass, muscle strength/power parameters, and physical function in a healthy cohort of Danish men and women across the lifespan.
Methods
Volunteers aged 20–93 years from the Copenhagen City Heart Study were invited to establish a Danish reference material (Copenhagen Sarcopenia Study) on lean mass characteristics [appendicular lean mass (ALM), iDXA, GE Lunar], muscle function [handgrip strength (HGS), Jamar dynamometer and leg extension power (LEP), Nottingham Power Rig], and physical function [30 s sit‐to‐stand test (STS), 10‐m maximal and habitual gait speed (GS)].
Results
A total of 1305 participants [729 women (age: 56.4 ± 18.9 years, height: 1.66 ± 0.01 m, body mass index: 24.6 ± 4.3 kg/m2 and 576 men, age: 57.0 ± 17.5 years, height: 1.80 ± 0.07 m, body mass index: 26.0 ± 3.9 kg/m2] completed all measurements and were included in the present analysis. Lean mass characteristics (TLM, ALM, and ALM/h2) decreased with increasing age in both men and women (P < 0.001). Men demonstrated larger absolute and relative total ALM and higher HGS and LEP compared with women at all age intervals (P < 0.001). HGS and LEP decreased progressively with age in both men and women (P < 0.01); 30 s STS performance, habitual GS, and maximal GS decreased at an accellerated rate of decline with increasing age in both men and women (P < 0.001). Habitual GS was reduced in men and women aged ≥70 years, while maximal GS was reduced from the age of ≥60 years compared with young adults (P < 0.001). Regardless of sex, 30 s STS was reduced from the age of ≥50 years compared with the young reference group (P < 0.001)
Conclusions
While the power‐based measurements (LEP and 30 s STS) started to decline already at age +50 years, less power‐based parameters (GS and HGS) and lean mass characteristics (TLM, ALM, and ALM/h2) remained unaltered until after the age of +70 years. Notably, the cut‐off thresholds derived in the present study differed from earlier reference data, which underlines the importance of obtaining updated and local reference materials.

Suetta, C., Haddock, B., Alcazar, J., Noerst, T., Hansen, O., Ludvig, H., Kamper, R. S., Schnohr, P., Prescott, E., Andersen, L. L., Frandsen, U., Aagaard, P., Bulow, J., Hovind, P., and Simonsen, L. ( 2019) The Copenhagen Sarcopenia Study: lean mass, strength, power, and physical function in a Danish cohort aged 20–93 years, Journal of Cachexia, Sarcopenia and Muscle, 10, 1316– 1329. https://doi.org/10.1002/jcsm.12477.

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     Article first published online:  17 June 2019

Hoi Yee Kwan, Matthew Maddocks, Claire M. Nolan, Sarah E. Jones, Suhani Patel, Ruth E. Barker, Samantha S.C. Kon, Michael I. Polkey, Paul Cullinan, William D.‐C. Man

The prognostic significance of weight loss in chronic obstructive pulmonary disease‐related cachexia: a prospective cohort study

Background
Cachexia is an important extra‐pulmonary manifestation of chronic obstructive pulmonary disease (COPD) presenting as unintentional weight loss and altered body composition. Previous studies have focused on the relative importance of body composition compared with body mass rather than the relative importance of dynamic compared with static measures. We aimed to determine the prevalence of cachexia and pre‐cachexia phenotypes in COPD and examine the associations between cachexia and its component features with all‐cause mortality.
Methods
We enrolled 1755 consecutive outpatients with stable COPD from two London centres between 2012 and 2017, stratified according to European Respiratory Society Task Force defined cachexia [unintentional weight loss >5% and low fat‐free mass index (FFMI)], pre‐cachexia (weight loss >5% but preserved FFMI), or no cachexia. The primary outcome was all‐cause mortality. We calculated hazard ratios (HRs) using Cox proportional hazards regression for cachexia classifications (cachexia, pre‐cachexia, and no cachexia) and component features (weight loss and FFMI) and mortality, adjusting for age, sex, body mass index, and disease‐specific prognostic markers.
Results
The prevalence of cachexia was 4.6% [95% confidence interval (CI): 3.6–5.6] and pre‐cachexia 1.6% (95% CI: 1.0–2.2). Prevalence was similar across sexes but increased with worsening Global Initiative for Chronic Obstructive Pulmonary Disease spirometric stage and Medical Research Council dyspnoea score (all P < 0.001). There were 313 (17.8%) deaths over a median (interquartile range) follow‐up duration 1089 (547–1704) days. Both cachexia [HR 1.98 (95% CI: 1.31–2.99), P = 0.002] and pre‐cachexia [HR 2.79 (95% CI: 1.48–5.29), P = 0.001] were associated with increased mortality. In multivariable analysis, the unintentional weight loss feature of cachexia was independently associated with mortality [HR 2.16 (95% CI: 1.31–3.08), P < 0.001], whereas low FFMI was not [HR 0.88 (95% CI: 0.64–1.20), P = 0.402]. Sensitivity analyses using body mass index‐specific, age‐specific, and gender‐specific low FFMI values found consistent findings.
Conclusions
Despite the low prevalence of cachexia and pre‐cachexia, both confer increased mortality risk in COPD, driven by the unintentional weight loss component. Our data suggest that low FFMI without concurrent weight loss may not confer the poor prognosis as previously reported for this group. Weight loss should be regularly monitored in practice and may represent an important target in COPD management. We propose the incorporation of weight monitoring into national and international COPD guidance.

Kwan, H. Y., Maddocks, M., Nolan, C. M., Jones, S. E., Patel, S., Barker, R. E., Kon, S. S. C., Polkey, M. I., Cullinan, P., and Man, W. D.‐C. ( 2019) The prognostic significance of weight loss in chronic obstructive pulmonary disease‐related cachexia: a prospective cohort study, Journal of Cachexia, Sarcopenia and Muscle, 10, 1330– 1338. https://doi.org/10.1002/jcsm.12463.

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     Article first published online:  21 August 2019

Bastian Kochlik, Wolfgang Stuetz, Karine Pérès, Sophie Pilleron, Catherine Féart, Francisco José García García, Stefania Bandinelli, David Gomez‐Cabrero, Leocadio Rodriguez‐Mañas, Tilman Grune, Daniela Weber

Associations of fat‐soluble micronutrients and redox biomarkers with frailty status in the FRAILOMIC initiative

Background
A poor fat‐soluble micronutrient (FMN) and a high oxidative stress status are associated with frailty. Our aim was to determine the cross‐sectional association of FMNs and oxidative stress biomarkers [protein carbonyls (PrCarb) and 3‐nitrotyrosine] with the frailty status in participants older than 65 years.
Methods
Plasma levels of vitamins A (retinol), D3, E (α‐tocopherol and γ‐tocopherol) and carotenoids (α‐carotene and β‐carotene, lycopene, lutein/zeaxanthin, and β‐cryptoxanthin), PrCarb, and 3‐nitrotyrosine were measured in 1450 individuals of the FRAILOMIC initiative. Participants were classified into robust, pre‐frail, and frail using Fried's frailty criteria. Associations between biomarkers and frailty status were assessed by general linear and logistic regression models, both adjusted for cohort, season of blood sampling, gender, age, height, weight, and smoking.
Results
Robust participants had significantly higher vitamin D3 and lutein/zeaxanthin concentrations than pre‐frail and frail subjects; had significantly higher γ‐tocopherol, α‐carotene, β‐carotene, lycopene, and β‐cryptoxanthin concentrations than frail subjects, and had significantly lower PrCarb concentrations than frail participants in multivariate linear models. Frail subjects were more likely to be in the lowest than in the highest tertile for vitamin D3 (adjusted odds ratio: 2.15; 95% confidence interval: 1.42–3.26), α‐tocopherol (2.12; 1.39–3.24), α‐carotene (1.69; 1.00–2.88), β‐carotene (1.84; 1.13–2.99), lycopene (1.94; 1.24–3.05), lutein/zeaxanthin (3.60; 2.34–5.53), and β‐cryptoxanthin (3.02; 1.95–4.69) and were more likely to be in the highest than in the lowest tertile for PrCarb (2.86; 1.82–4.49) than robust subjects in multivariate regression models.
Conclusions
Our study indicates that both low FMN and high PrCarb concentrations are associated with pre‐frailty and frailty.

Kochlik, B., Stuetz, W., Pérès, K., Pilleron, S., Féart, C., García García, F. J., Bandinelli, S., Gomez‐Cabrero, D., Rodriguez‐Mañas, L., Grune, T., and Weber, D. ( 2019) Associations of fat‐soluble micronutrients and redox biomarkers with frailty status in the FRAILOMIC initiative, Journal of Cachexia, Sarcopenia and Muscle, 10, 1339– 1346. https://doi.org/10.1002/jcsm.12479.

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     Article first published online:  15 July 2019

Ana Anoveros‐Barrera, Amritpal S. Bhullar, Cynthia Stretch, Nina Esfandiari, Abha R. Dunichand‐Hoedl, Karen J.B. Martins, David Bigam, Rachel G. Khadaroo, Todd McMullen, Oliver F. Bathe, Sambasivarao Damaraju, Richard J. Skipworth, Charles T. Putman, Vickie E. Baracos, Vera C. Mazurak

Clinical and biological characterization of skeletal muscle tissue biopsies of surgical cancer patients

Background
Researchers increasingly use intraoperative muscle biopsy to investigate mechanisms of skeletal muscle atrophy in patients with cancer. Muscles have been assessed for morphological, cellular, and biochemical features. The aim of this study was to conduct a state‐of‐the‐science review of this literature and, secondly, to evaluate clinical and biological variation in biopsies of rectus abdominis (RA) muscle from a cohort of patients with malignancies.
Methods
Literature was searched for reports on muscle biopsies from patients with a cancer diagnosis. Quality of reports and risk of bias were assessed. Data abstracted included patient characteristics and diagnoses, sample size, tissue collection and biobanking procedures, and results. A cohort of cancer patients (n = 190, 88% gastrointestinal malignancies), who underwent open abdominal surgery as part of their clinical care, consented to RA biopsy from the site of incision. Computed tomography (CT) scans were used to quantify total abdominal muscle and RA cross‐sectional areas and radiodensity. Biopsies were assessed for muscle fibre area (μm2), fibre types, myosin heavy chain isoforms, and expression of genes selected for their involvement in catabolic pathways of muscle.
Results
Muscle biopsy occurred in 59 studies (total N = 1585 participants). RA was biopsied intraoperatively in 40 studies (67%), followed by quadriceps (26%; percutaneous biopsy) and other muscles (7%). Cancer site and stage, % of male participants, and age were highly variable between studies. Details regarding patient medical history and biopsy procedures were frequently absent. Lack of description of the population(s) sampled and low sample size contributed to low quality and risk of bias. Weight‐losing cases were compared with weight stable cancer or healthy controls without considering a measure of muscle mass in 21 out of 44 studies. In the cohort of patients providing biopsy for this study, 78% of patients had preoperative CT scans and a high proportion (64%) met published criteria for sarcopenia. Fibre type distribution in RA was type I (46% ± 13), hybrid type I/IIA (1% ± 1), type IIA (36% ± 10), hybrid type IIA/D (15% ± 14), and type IID (2% ± 5). Sexual dimorphism was prominent in RA CT cross‐sectional area, mean fibre cross‐sectional area, and in expression of genes associated with muscle growth, apoptosis, and inflammation (P < 0.05). Medical history revealed multiple co‐morbid conditions and medications.
Conclusions
Continued collaboration between researchers and cancer surgeons enables a more complete understanding of mechanisms of cancer‐associated muscle atrophy. Standardization of biobanking practices, tissue manipulation, patient characterization, and classification will enhance the consistency, reliability, and comparability of future studies.

Anoveros‐Barrera, A., Bhullar, A. S., Stretch, C., Esfandiari, N., Dunichand‐Hoedl, A. R., Martins, K. J. B., Bigam, D., Khadaroo, R. G., McMullen, T., Bathe, O. F., Damaraju, S., Skipworth, R. J., Putman, C. T., Baracos, V. E., and Mazurak, V. C. ( 2019) Clinical and biological characterization of skeletal muscle tissue biopsies of surgical cancer patients, Journal of Cachexia, Sarcopenia and Muscle, 10, 1356– 1377. https://doi.org/10.1002/jcsm.12466.

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     Article first published online:  10 December 2019

Markus S. Anker, Stefan D. Anker, Andrew J.S. Coats, Stephan von Haehling

Abstract

Anker, M. S., Anker, S. D., Coats, A. J. S., and von Haehling, S. ( 2019) The Journal of Cachexia, Sarcopenia and Muscle stays the front‐runner in geriatrics and gerontology, Journal of Cachexia, Sarcopenia and Muscle, 10, 1151– 1164. https://doi.org/10.1002/jcsm.12518.

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