Article first published online:  01 December 2019

Daniel X.M. Wang, Jessica Yao, Yasar Zirek, Esmee M. Reijnierse, Andrea B. Maier

Muscle mass, strength, and physical performance predicting activities of daily living: a meta‐analysis
Background
Activities of daily living (ADLs) and instrumental activities of daily living (IADLs) are essential for independent living and are predictors of morbidity and mortality in older populations. Older adults who are dependent in ADLs and IADLs are also more likely to have poor muscle measures defined as low muscle mass, muscle strength, and physical performance, which further limit their ability to perform activities. The aim of this systematic review and meta‐analysis was to determine if muscle measures are predictive of ADL and IADL in older populations.
Methods
A systematic search was conducted using four databases (MEDLINE, EMBASE, Cochrane, and CINAHL) from date of inception to 7 June 2018. Longitudinal cohorts were included that reported baseline muscle measures defined by muscle mass, muscle strength, and physical performance in conjunction with prospective ADL or IADL in participants aged 65 years and older at follow‐up. Meta‐analyses were conducted using a random effect model.
Results
Of the 7760 articles screened, 83 articles were included for the systematic review and involved a total of 108 428 (54.8% female) participants with a follow‐up duration ranging from 11 days to 25 years. Low muscle mass was positively associated with ADL dependency in 5/9 articles and 5/5 for IADL dependency. Low muscle strength was associated with ADL dependency in 22/34 articles and IADL dependency in 8/9 articles. Low physical performance was associated with ADL dependency in 37/49 articles and with IADL dependency in 9/11 articles. Forty‐five articles were pooled into the meta‐analyses, 36 reported ADL, 11 reported IADL, and 2 reported ADL and IADL as a composite outcome. Low muscle mass was associated with worsening ADL (pooled odds ratio (95% confidence interval) 3.19 (1.29–7.92)) and worsening IADL (1.28 (1.02–1.61)). Low handgrip strength was associated with both worsening ADL and IADL (1.51 (1.34–1.70); 1.59 (1.04–2.31) respectively). Low scores on the short physical performance battery and gait speed were associated with worsening ADL (3.49 (2.47–4.92); 2.33 (1.58–3.44) respectively) and IADL (3.09 (1.06–8.98); 1.93 (1.69–2.21) respectively). Low one leg balance (2.74 (1.31–5.72)), timed up and go (3.41 (1.86–6.28)), and chair stand test time (1.90 (1.63–2.21)) were associated with worsening ADL.
Conclusions
Muscle measures at baseline are predictors of future ADL and IADL dependence in the older adult population.

Wang, D. X. M., Yao, J., Zirek, Y., Reijnierse, E. M., and Maier, A. B. ( 2020) Muscle mass, strength, and physical performance predicting activities of daily living: a meta‐analysis, Journal of Cachexia, Sarcopenia and Muscle, 11: 3– 25. https://doi.org/10.1002/jcsm.12502.

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     Article first published online:  29 January 2020

Yuya Watanabe, Yosuke Yamada, Tsukasa Yoshida, Keiichi Yokoyama, Motoko Miyake, Emi Yamagata, Minoru Yamada, Yasuko Yoshinaka, Misaka Kimura for Kyoto‐Kameoka Study Group

Comprehensive geriatric intervention in community‐dwelling older adults: a cluster‐randomized controlled trial
Background
In longevity societies, one of the most serious social issues is sarcopenia and/or frailty. Preventing them is important for maintaining independence and quality of life in the older population. This study investigated the effect of a self‐monitoring comprehensive geriatric intervention programme (CGIP) on physical function and muscle size in community‐dwelling older adults. We compared the effects of a CGIP using weekly class‐styled (CS) sessions and a home‐based (HB) programme.
Methods
The 526 participants were randomized into one of two groups (CS 251, HB 275) based on their residential districts. We conducted a 12 week CGIP, which consisted of low‐load resistance exercise, physical activity increments, oral function improvements, and a nutritional guide. All participants were encouraged to attend two 90 min lectures that included instructions on the CGIP. They were provided with exercise materials (triaxial‐accelerometers/pedometers, ankle weights, and elastic bands) and diary logs. The CS group attended 90 min weekly sessions and independently executed the programme on other days, whereas the HB group only received instructions on how to execute the programme. Physical functions, such as knee extension strength (KES), normal and maximum walking speed, the timed up‐and‐go test, and anterior thigh muscle thickness (MT), were measured and analysed using intention‐to‐treat analysis before and after the 12 week intervention.
Results
Of the 526 participants identified, 517 (CS 243 age 74.0 ± 5.4 women 57.2%, HB 274 age 74.0 ± 5.6 women 58.8%) were enrolled. Nine (CS 8, HB 1) were excluded from the analysis because they did not participate in the pre‐intervention measurements. Both interventions significantly improved KES (CS 18.5%, HB 10.6%), normal walking speed (CS 3.7%, HB 2.8%), and MT (CS 3.2%, HB 3.5%). Greater improvement of KES was observed in the CS group (P = 0.003). Maximum walking speed (CS 4.7%, HB 1.8%; P = 0.001) and timed up‐and‐go (CS −4.7%, HB −0.2%; P < 0.001) significantly improved in the CS group only.
Conclusions
The intervention was effective in preventing sarcopenia and/or frailty. Most physical functions and MT improved after both interventions. The HB intervention is cost‐effective and may help prevent sarcopenia and/or frailty in the large older population.

Watanabe, Y., Yamada, Y., Yoshida, T., Yokoyama, K., Miyake, M., Yamagata, E., Yamada, M., Yoshinaka, Y., Kimura, M., and for Kyoto‐Kameoka Study Group ( 2020) Comprehensive geriatric intervention in community‐dwelling older adults: a cluster‐randomized controlled trial, Journal of Cachexia, Sarcopenia and Muscle, 11: 26– 37. https://doi.org/10.1002/jcsm.12504.

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     Article first published online:  04 December 2019

Francesco Landi, Sara Salini, Maria Beatrice Zazzara, Anna Maria Martone, Sofia Fabrizi, Mariangela Bianchi, Matteo Tosato, Anna Picca, Riccardo Calvani, Emanuele Marzetti

Relationship between pulmonary function and physical performance among community‐living people: results from Look‐up 7+ study
Background
In longevity societies, one of the most serious social issues is sarcopenia and/or frailty. Preventing them is important for maintaining independence and quality of life in the older population. This study investigated the effect of a self‐monitoring comprehensive geriatric intervention programme (CGIP) on physical function and muscle size in community‐dwelling older adults. We compared the effects of a CGIP using weekly class‐styled (CS) sessions and a home‐based (HB) programme.
Methods
The 526 participants were randomized into one of two groups (CS 251, HB 275) based on their residential districts. We conducted a 12 week CGIP, which consisted of low‐load resistance exercise, physical activity increments, oral function improvements, and a nutritional guide. All participants were encouraged to attend two 90 min lectures that included instructions on the CGIP. They were provided with exercise materials (triaxial‐accelerometers/pedometers, ankle weights, and elastic bands) and diary logs. The CS group attended 90 min weekly sessions and independently executed the programme on other days, whereas the HB group only received instructions on how to execute the programme. Physical functions, such as knee extension strength (KES), normal and maximum walking speed, the timed up‐and‐go test, and anterior thigh muscle thickness (MT), were measured and analysed using intention‐to‐treat analysis before and after the 12 week intervention.
Results
Of the 526 participants identified, 517 (CS 243 age 74.0 ± 5.4 women 57.2%, HB 274 age 74.0 ± 5.6 women 58.8%) were enrolled. Nine (CS 8, HB 1) were excluded from the analysis because they did not participate in the pre‐intervention measurements. Both interventions significantly improved KES (CS 18.5%, HB 10.6%), normal walking speed (CS 3.7%, HB 2.8%), and MT (CS 3.2%, HB 3.5%). Greater improvement of KES was observed in the CS group (P = 0.003). Maximum walking speed (CS 4.7%, HB 1.8%; P = 0.001) and timed up‐and‐go (CS −4.7%, HB −0.2%; P < 0.001) significantly improved in the CS group only.
Conclusions
The intervention was effective in preventing sarcopenia and/or frailty. Most physical functions and MT improved after both interventions. The HB intervention is cost‐effective and may help prevent sarcopenia and/or frailty in the large older population.

Landi, F., Salini, S., Zazzara, M. B., Martone, A. M., Fabrizi, S., Bianchi, M., Tosato, M., Picca, A., Calvani, R., and Marzetti, E. ( 2020) Relationship between pulmonary function and physical performance among community‐living people: results from Look‐up 7+ study, Journal of Cachexia, Sarcopenia and Muscle, 11: 38– 45. https://doi.org/10.1002/jcsm.12485.

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     Article first published online:  22 August 2019

Kazuki Uemura, Takehiko Doi, Kota Tsutsumimoto, Sho Nakakubo, Min‐Ji Kim, Satoshi Kurita, Hideaki Ishii, Hiroyuki Shimada

Predictivity of bioimpedance phase angle for incident disability in older adults
Background
Bioelectrical impedance analysis (BIA)‐derived phase angle is expected to be an efficient prognostic marker of health adverse events with aging as an alternative of muscle mass. We aimed to examine the predictive ability of phase angle for incident disability in community‐dwelling elderly and determine the optimal cut‐off values.
Methods
Community‐dwelling elderly aged ≥65 years (n = 4452; mean age = 71.8 ± 5.3 years, 48.3% women) without disability at baseline participated in this prospective cohort study. Phase angle and appendicular skeletal muscle mass (ASM) were examined using a multi‐frequency BIA at baseline. Other potential confounding factors (demographics, cognitive function, depressive symptoms, medications, and physical performance) were also assessed. Incident disability was monitored on the basis of long‐term care insurance certification.
Results
Over a follow‐up of 24 months, 4.0% (n = 174) experienced disability, with an overall incidence rate of 20.6 per 1000 person‐years. The Cox hazard regression analysis showed that phase angle, as a continuous variable, was independently associated with incident disability after adjusting the covariates [male: hazard ratios (HRs) = 0.61, 95% confidence interval (CI) = 0.37–0.98; female: HR = 0.58, 95% CI = 0.37–0.90], although body mass index adjusted ASM was not. Receiver operating characteristic analysis indicated moderate predictive abilities of phase angle for incident disability [male: area under the receiver operating characteristic curve (AUC) = 0.76, 95% CI = 0.70–0.83; female: AUC = 0.71, 95% CI = 0.65–0.76], while those of body mass index adjusted ASM were low (male: AUC = 0.59, 95% CI = 0.521–0.66; female: AUC = 0.58, 95% CI = 0.52–0.63). Multivariate Cox regression analysis showed that low phase angle categorized by cut‐off value (male, ≤4.95°; female, ≤4.35°) was independently related to increased risk of incident disability (HR = 1.95, 95% CI = 1.37–2.78).
Conclusions
Lower phase angle independently predicts the incident disability separately from known risk factors. BIA‐derived phase angle can be used as a valuable and simple prognostic tool to identify the elderly at risk of disability as targets of preventive treatment.

Uemura, K., Doi, T., Tsutsumimoto, K., Nakakubo, S., Kim, M.‐J., Kurita, S., Ishii, H., and Shimada, H. ( 2020) Predictivity of bioimpedance phase angle for incident disability in older adults, Journal of Cachexia, Sarcopenia and Muscle, 11: 46– 54. https://doi.org/10.1002/jcsm.12492.

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     Article first published online:  17 October 2019

Kate A. Duchowny, Katherine E. Peters, Steven R. Cummings, Eric S. Orwoll, Andrew R. Hoffman, Kristine E. Ensrud, Jane A. Cauley, William J. Evans, Peggy M. Cawthon for the Osteoporotic Fractures in Men (MrOS) Study Research Group

Association of change in muscle mass assessed by D3‐creatine dilution with changes in grip strength and walking speed
Background
Muscle mass declines with age. However, common assessments used to quantify muscle mass are indirect. The D3‐creatine (D3Cr) dilution method is a direct assessment of muscle mass; however, longitudinal changes have not been examined in relation to changes in other measures of muscle mass, strength, and performance.
Methods
A convenience sample of 40 men from the Osteoporotic Fractures in Men Study (mean age = 83.3 years, standard deviation = 3.9) underwent repeat assessment of D3Cr muscle mass, dual‐energy X‐ray absorptiometry (DXA) lean mass, grip strength, and walking speed at two time points approximately 1.6 years apart (2014–2016). One‐sample t‐tests and Pearson correlations were used to examine changes in DXA total body lean mass, DXA appendicular lean mass/height2, DXA appendicular lean mass/weight, D3Cr muscle mass, D3Cr muscle mass/weight, grip strength, walking speed, and weight.
Results
D3‐creatine muscle mass, D3Cr muscle mass/weight, grip strength, and walking speed all significantly declined (all P < 0.01). The change in DXA measures of lean mass was moderately correlated with changes in D3Cr muscle mass. There was no significant correlation between the change in DXA measures of lean mass and change in walking speed (all P > 0.05). The change in D3Cr muscle mass/weight was moderately correlated with change in walking speed (r = 0.33, P < .05). The change in grip strength was weakly correlated with the change in DXA measures of lean mass and D3Cr muscle mass (r = 0.19–0.32).
Conclusions
The results of our study provide new insights regarding the decline in muscle strength and D3Cr muscle mass. The D3Cr method may be a feasible tool to measure declines in muscle mass over time.

Duchowny, K. A., Peters, K. E., Cummings, S. R., Orwoll, E. S., Hoffman, A. R., Ensrud, K. E., Cauley, J. A., Evans, W. J., Cawthon, P. M., and for the Osteoporotic Fractures in Men (MrOS) Study Research Group ( 2020) Association of change in muscle mass assessed by D3‐creatine dilution with changes in grip strength and walking speed, Journal of Cachexia, Sarcopenia and Muscle, 11: 55– 61. https://doi.org/10.1002/jcsm.12494.

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     Article first published online:  30 December 2019

Richard M. Dodds, Antoneta Granic, Sian M. Robinson, Avan A. Sayer

Sarcopenia, long‐term conditions, and multimorbidity: findings from UK Biobank participants
Background
Sarcopenia, the loss of muscle strength and mass, predicts adverse outcomes and becomes common with age. There is recognition that sarcopenia may occur at younger ages in those with long‐term conditions (LTCs) as well as those with multimorbidity (the presence of two or more LTCs), but their relationships have been little explored. Our aims were to describe the prevalence of sarcopenia in UK Biobank, a large sample of men and women aged 40–70 years, and to explore relationships with different categories of LTCs and multimorbidity.
Methods
We used data from 499 046 participants in the baseline of UK Biobank. Our main outcome was probable sarcopenia based on maximum grip strength below sex‐specific cut‐points. Participants' LTCs were recorded during an interview and categorized against a hierarchy. We used logistic regression to examine the independent associations between each category of LTCs and probable sarcopenia, including adjustment for age, sex, and body mass index. We also examined the association with multimorbidity.
Results
Probable sarcopenia had an overall prevalence of 5.3% and increased with age. The categories with the strongest associations with probable sarcopenia were musculoskeletal/trauma [OR 2.17 (95% CI: 2.11, 2.23)], endocrine/diabetes [OR 1.49 (95% CI: 1.45, 1.55)], and neurological/psychiatric [OR 1.39 (95% CI: 1.34, 1.43)] LTCs. Almost half of the sample (44.5%) had multimorbidity, and they were at nearly twice the odds of probable sarcopenia [OR 1.96 (95% CI: 1.91, 2.02)] compared with those without.
Conclusions
We have shown an overall prevalence of 5.3% of probable sarcopenia at ages 40–70 in UK Biobank. The risk of probable sarcopenia was higher in those with some categories of LTCs, suggesting that these groups may stand to benefit from assessment of sarcopenia, during mid‐life as well as old age.

Dodds, R. M., Granic, A., Robinson, S. M., and Sayer, A. A. ( 2020) Sarcopenia, long‐term conditions, and multimorbidity: findings from UK Biobank participants, Journal of Cachexia, Sarcopenia and Muscle, 11: 62– 68. https://doi.org/10.1002/jcsm.12503.

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     Article first published online:  21 August 2019

Rima Nasrah, Christina Van Der Borch

Defining barriers to implementation of nutritional advice in patients with cachexia
Background
Cancer cachexia is a multidimensional wasting syndrome and a reduced dietary intake is both common and strongly correlated with degree of weight loss. Many patients with cachexia do not achieve recommended dietary intake even after nutritional counselling. Prior reports suggest this is likely due to barrier symptoms, but other potential contributory factors have not been studied in detail.
Methods
Dietitian‐assigned barriers to successful nutritional intervention were recorded at each visit in all patients attending a multidisciplinary clinic for management of cancer cachexia. The barriers were grouped into 15 categories and classified as either symptom‐related or not symptom‐related. In addition, symptom scores, dietary intake, and weight change were recorded.
Results
Data on 94 new patients showed that 89% of patients had at least one major barrier. Four of the five most common barriers and 65% of all barriers identified were not symptom‐related. Over sequential visits the specific barrier(s) in any one patient changed approximately 50% of the time. However, the presence of barriers did not render patients refractory to nutritional intervention and with intervention from the CNR‐JGH team, mean dietary intake increased significantly.
Conclusions
In advanced cancer patients with cachexia, non‐symptom‐related barriers to nutritional intervention are more common than symptom‐related. Barriers are dynamic, and repeated careful evaluation over time is required to achieve optimal impact with nutritional intervention in cancer cachexia. Members of the multidisciplinary team need appropriate expertise to address the barriers identified and achieve optimal results with nutritional intervention.

Nasrah, R., Van Der Borch, C., Kanbalian, M., and Jagoe, R. T. ( 2020) Defining barriers to implementation of nutritional advice in patients with cachexia, Journal of Cachexia, Sarcopenia and Muscle, 11: 69– 78. https://doi.org/10.1002/jcsm.12490.

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     Article first published online:  20 August 2019

Jack O. Garnham,Lee D. Roberts, Talia Caspi, Moza M. Al‐Owais, Max Bullock, Peter P. Swoboda, Aaron Koshy, John Gierula, Maria F. Paton, Richard M. Cubbon, Mark T. Kearney, T. Scott Bowen, Klaus K. Witte

Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure
Background
Previous studies in heart failure with reduced ejection fraction (HFrEF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF.
Methods
Mitochondrial respiration, enzyme activity, and gene expression were examined in pectoralis major biopsies from age‐matched male (n = 45) and female (n = 11) patients with HFrEF and healthy‐matched male (n = 24) and female (n = 11) controls. Mitochondrial variables were compared between sex and related to peak exercise capacity.
Results
Compared with sex‐matched controls, complex I mitochondrial oxygen flux was 17% (P = 0.030) and 29% (P = 0.013) lower in male and female patients with HFrEF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFrEF patients had a 32% (P = 0.023) lower mitochondrial content compared with controls. However, after adjusting for mitochondrial content, male patients demonstrated lower complex I function by 15% (P = 0.030). Expression of key mitochondrial genes regulating organelle dynamics and maintenance (i.e. optic atrophy 1, peroxisome proliferator‐activated receptor γ coactivator‐1α, NADH:ubiquinone oxidoreductase core subunit S1/S3, and superoxide dismutase 2) were selectively lower in female HFrEF patients.
Conclusions
These data provide novel evidence that HFrEF induces divergent sex‐specific mitochondrial phenotypes in skeletal muscle that predispose towards exercise intolerance, impacting mitochondrial ‘quantity' in female patients and mitochondrial ‘quality' in male patients. Therapeutic strategies to improve exercise tolerance in HFrEF should consider targeting sex‐specific mitochondrial abnormalities in skeletal muscle.

Garnham, J. O., Roberts, L. D., Caspi, T., Al‐Owais, M. M., Bullock, M., Swoboda, P. P., Koshy, A., Gierula, J., Paton, M. F., Cubbon, R. M., Kearney, M. T., Bowen, T. S., and Witte, K. K. ( 2020) Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure, Journal of Cachexia, Sarcopenia and Muscle, 11: 79– 88. https://doi.org/10.1002/jcsm.12488.

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     Article first published online:  19 November 2019

Ligia M. Antunes‐Correa, Patricia F. Trevizan, Aline V.N. Bacurau, Larissa Ferreira‐Santos, João L.P. Gomes, Ursula Urias, Patricia A. Oliveira, Maria Janieire N.N. Alves, Dirceu R. de Almeida, Patricia C. Brum, Edilamar M. Oliveira, Ludhmila Hajjar, Roberto Kalil Filho, Carlos Eduardo Negrão

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure
Background
The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA‐1 expression and downstream‐associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients.
Methods
Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II–III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months.
Results
Thirty‐three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA‐1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = −15 ± 0.03%), and tended to increase the p‐AKTser473/AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = −40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross‐sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA‐1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51).
Conclusions
AET upregulates microRNA‐1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K‐AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA‐1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross‐sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA‐1 and in the downstream‐associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle.

Antunes‐Correa, L. M., Trevizan, P. F., Bacurau, A. V. N., Ferreira‐Santos, L., Gomes, J. L. P., Urias, U., Oliveira, P. A., Alves, M. J. N. N., de Almeida, D. R., Brum, P. C., Oliveira, E. M., Hajjar, L., Kalil Filho, R., and Negrão, C. E. ( 2020) Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure, Journal of Cachexia, Sarcopenia and Muscle, 11: 89– 102. https://doi.org/10.1002/jcsm.12495.

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     Article first published online:  23 August 2019

Alexander Hahn, Melanie Kny, Cristina Pablo‐Tortola, Mihail Todiras, Michael Willenbrock, Sibylle Schmidt, Katrin Schmoeckel, Ilka Jorde, Marcel Nowak, Ernst Jarosch, Thomas Sommer, Barbara M. Bröker, Stephan B. Felix, Claus Scheidereit, Steffen Weber‐Carstens, Christian Butter, Friedrich C. Luft, Jens Fielitz

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

Background
Critically ill patients frequently develop muscle atrophy and weakness in the intensive‐care‐unit setting [intensive care unit‐acquired weakness (ICUAW)]. Sepsis, systemic inflammation, and acute‐phase response are major risk factors. We reported earlier that the acute‐phase protein serum amyloid A1 (SAA1) is increased and accumulates in muscle of ICUAW patients, but its relevance was unknown. Our objectives were to identify SAA1 receptors and their downstream signalling pathways in myocytes and skeletal muscle and to investigate the role of SAA1 in inflammation‐induced muscle atrophy.
Methods
We performed cell‐based in vitro and animal in vivo experiments. The atrophic effect of SAA1 on differentiated C2C12 myotubes was investigated by analysing gene expression, protein content, and the atrophy phenotype. We used the cecal ligation and puncture model to induce polymicrobial sepsis in wild type mice, which were treated with the IкB kinase inhibitor Bristol‐Myers Squibb (BMS)‐345541 or vehicle. Morphological and molecular analyses were used to investigate the phenotype of inflammation‐induced muscle atrophy and the effects of BMS‐345541 treatment.
Results
The SAA1 receptors Tlr2, Tlr4, Cd36, P2rx7, Vimp, and Scarb1 were all expressed in myocytes and skeletal muscle. Treatment of differentiated C2C12 myotubes with recombinant SAA1 caused myotube atrophy and increased interleukin 6 (Il6) gene expression. These effects were mediated by Toll‐like receptors (TLR) 2 and 4. SAA1 increased the phosphorylation and activity of the transcription factor nuclear factor ‘kappa‐light‐chain‐enhancer’ of activated B‐cells (NF‐κB) p65 via TLR2 and TLR4 leading to an increased binding of NF‐κB to NF‐κB response elements in the promoter region of its target genes resulting in an increased expression of NF‐κB target genes. In polymicrobial sepsis, skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with the atrophy response. Inhibition of NF‐κB signalling by BMS‐345541 increased survival (28.6% vs. 91.7%, P < 0.01). BMS‐345541 diminished inflammation‐induced atrophy as shown by a reduced weight loss of the gastrocnemius/plantaris (vehicle: −21.2% and BMS‐345541: −10.4%; P < 0.05), tibialis anterior (vehicle: −22.7% and BMS‐345541: −17.1%; P < 0.05) and soleus (vehicle: −21.1% and BMS‐345541: −11.3%; P < 0.05) in septic mice. Analysis of the fiber type specific myocyte cross‐sectional area showed that BMS‐345541 reduced inflammation‐induced atrophy of slow/type I and fast/type II myofibers compared with vehicle‐treated septic mice. BMS‐345541 reversed the inflammation‐induced atrophy program as indicated by a reduced expression of the atrogenes Trim63/MuRF1, Fbxo32/Atrogin1, and Fbxo30/MuSA1.
Conclusions
SAA1 activates the TLR2/TLR4//NF‐κB p65 signalling pathway to cause myocyte atrophy. Systemic inhibition of the NF‐κB pathway reduced muscle atrophy and increased survival of septic mice. The SAA1/TLR2/TLR4//NF‐κB p65 atrophy pathway could have utility in combatting ICUAW.

Hahn, A., Kny, M., Pablo‐Tortola, C., Todiras, M., Willenbrock, M., Schmidt, S., Schmoeckel, K., Jorde, I., Nowak, M., Jarosch, E., Sommer, T., Bröker, B. M., Felix, S. B., Scheidereit, C., Weber‐Carstens, S., Butter, C., Luft, F. C., and Fielitz, J. ( 2019) Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors, Journal of Cachexia, Sarcopenia and Muscle, XXX, doi: https://doi.org/10.1002/jcsm.12491.

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     Article first published online:  13 November 2019

Wai W. Cheung, Sheng Hao, Zhen Wang, Wei Ding, Ronghao Zheng, Alex Gonzalez, Jian‐Ying Zhan, Ping Zhou, Shiping Li, Mary C. Esparza, Hal M. Hoffman, Richard L. Lieber, Robert H. Mak

Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis‐associated cachexia
Background
Ctns−/− mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns−/− mice are 25(OH)D3 and 1,25(OH)2D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns−/− mice.
Methods
Twelve‐month‐old Ctns−/− mice and wild‐type controls were treated with 25(OH)D3 and 1,25(OH)2D3 (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns−/− mice using RNAseq.
Results
Supplementation of 25(OH)D3 and 1,25(OH)2D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2D3 in Ctns−/− mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns−/− mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP‐1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF‐κB pathway) in inguinal white adipose tissue in Ctns−/− mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns−/− mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL‐1β, IL‐6, and TNF‐α as well as an increased gene expression of Murf‐2, atrogin‐1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns−/− mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns−/− mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2D3 normalized the top 20 differentially expressed genes in Ctns−/− mice.
Conclusions
We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns−/− mice via multiple cellular and molecular mechanisms.

Cheung, W. W., Hao, S., Wang, Z., Ding, W., Zheng, R., Gonzalez, A., Zhan, J.‐Y., Zhou, P., Li, S., Esparza, M. C., Hoffman, H. M., Lieber, R. L., and Mak, R. H. ( 2020) Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis‐associated cachexia, Journal of Cachexia, Sarcopenia and Muscle, 11: 120– 134. https://doi.org/10.1002/jcsm.12497.

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     Article first published online:  28 August 2019

Ulrich T. Hacker, Dirk Hasenclever, Nicolas Linder, Gertraud Stocker, Hyun‐Cheol Chung, Yoon‐Koo Kang, Markus Moehler, Harald Busse, Florian Lordick

Prognostic role of body composition parameters in gastric/gastroesophageal junction cancer patients from the EXPAND trial
Background
Body fat and/or muscle composition influences prognosis in several cancer types. For advanced gastric and gastroesophageal junction cancer, we investigated which body composition parameters carry prognostic information beyond well‐established clinical parameters using robust model selection strategy such that parameters identified can be expected to generalize and to be reproducible beyond our particular data set. Then we modelled how differences in these parameters translate into survival outcomes.
Methods
Fat and muscle parameters were measured on baseline computed tomography scans in 761 patients with advanced gastric or gastroesophageal junction cancer from the phase III EXPAND trial, undergoing first‐line chemotherapy. Cox regression analysis for overall survival (OS) and progression‐free survival (PFS) included body composition parameters and clinical prognostic factors. All continuous variables were entered linearly into the model as there was no evidence of non‐linear prognostic impact. For transferability, the final model included only parameters that were picked by Bayesian information criterion model selection followed by bootstrap analysis to identify the most robust model.
Results
Muscle and fat parameters formed correlation clusters without relevant between‐cluster correlation. Mean muscle attenuation (MA) clusters with the fat parameters. In multivariate analysis, MA was prognostic for OS (P < 0.0001) but not for PFS, while skeletal muscle index was prognostic for PFS (P = 0.02) but not for OS. Worse performance status Eastern Cooperative Oncology Group (ECOG 1/0), younger age (on a linear scale), and the number of metastatic sites were strong negative clinical prognostic factors for both OS and PFS. MA remained in the model for OS (P = 0.0001) following Bayesian information criterion model selection in contrast to skeletal muscle index that remained prognostic for PFS (P = 0.009). Applying stricter criteria for transferability, MA represented the only prognostic body composition parameter for OS, selected in >80% of bootstrap replicates. Finally, Cox model‐derived survival curves indicated that large differences in MA translate into only moderate differences in expected OS in this cohort.
Conclusions
Among body composition parameters, only MA has robust prognostic impact for OS. Data suggest that treatment approaches targeting muscle quality are unlikely to prolong OS noticeably on their own in advanced gastric cancer patients, indicating that multimodal approaches should be pursued in the future.

Hacker, U. T., Hasenclever, D., Linder, N., Stocker, G., Chung, H.‐C., Kang, Y.‐K., Moehler, M., Busse, H., and Lordick, F. ( 2020) Prognostic role of body composition parameters in gastric/gastroesophageal junction cancer patients from the EXPAND trial, Journal of Cachexia, Sarcopenia and Muscle, 11: 135– 144. https://doi.org/10.1002/jcsm.12484.

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     Article first published online:  19 September 2019

Anna C.H. Willemsen, Ann Hoeben, Roy I. Lalisang, Ardy Van Helvoort, Frederik W.R. Wesseling, Frank Hoebers, Laura W.J. Baijens, Annemie M.W.J. Schols

Disease‐induced and treatment‐induced alterations in body composition in locally advanced head and neck squamous cell carcinoma
Background
Chemoradiation or bioradiation treatment (CRT/BRT) of locally advanced head and neck squamous cell carcinoma (LAHNSCC) comes with high toxicity rates, often leading to temporary tube feeding (TF) dependency. Cachexia is a common problem in LAHNSCC. Yet changes in body composition and muscle weakness during CRT/BRT are underexplored. Strong evidence on the effect of TF on body composition during treatment is lacking. The aim of this cohort study was to assess (i) the relationship of fat‐free mass index (FFMI) and handgrip strength (HGS) with CRT/BRT toxicity and outcome, (ii) body composition in patients treated with chemoradiation (cisplatin) vs. bioradiation (cetuximab), and (iii) the effect of the current TF regime on body composition and muscle strength.
Methods
Locally advanced head and neck squamous cell carcinoma patients treated with CRT/BRT between January 2013 and December 2016 were included (n = 137). Baseline measurements of body composition (bioelectrical impedance analysis) and HGS were performed. Toxicity grades (Common Terminology Criteria for Adverse Events) were scored. In a subset of 69 patients, weight loss, body composition, and HGS were additionally assessed during and after CRT/BRT. TF was initiated according to the Dutch guidelines for malnutrition.
Results
In this cohort (68% male, mean age 59 ± 8 years), the incidence of baseline muscle wasting, defined as FFMI < P10, was 29%. Muscle wasting was present in 23 of 100 (23%) chemoradiation patients and 17 of 37 (46%) bioradiation patients (P = 0.009). Muscle‐wasted patients required more unplanned hospitalizations during CRT (P = 0.035). In the chemoradiation subset, dose‐limiting toxicity was significantly higher in wasted vs. non‐wasted patients (57% vs. 25%, P = 0.004). Median follow‐up was 32 months. Multivariate Cox regression analysis identified muscle wasting as independent unfavourable prognostic factor for overall survival [hazard ratio 2.1 (95% CI 1.1–4.1), P = 0.022] and cisplatin as favourable prognostic factor [hazard ratio 0.3 (95% CI 0.2–0.6), P = 0.001]. Weight and HGS significantly decreased during CRT/BRT, −3.7 ± 3.5 kg (P < 0.001) and −3.1 ± 6.0 kg (P < 0.001), respectively. Sixty‐four per cent of the patients required TF 21 days (range 0–59) after CRT/BRT initiation. Total weight loss during CRT/BRT was significantly (P = 0.007) higher in the total oral diet group (5.5 ± 3.7 kg) compared with the TF group (3.0 ± 3.2 kg). Loss of FFM and HGS was similar in both groups.
Conclusions
In LAHNSCC patients undergoing CRT/BRT, FFMI < P10 is an unfavourable prognostic factor for overall survival, treatment toxicity, and tolerance. Patients experience significant weight and FFM loss during treatment. Current TF regime attenuates weight loss but does not overcome loss of muscle mass and function during therapy. Future interventions should consider nutritional intake and additional strategies specifically targeting metabolism, loss of muscle mass, and function.

Willemsen, A. C. H., Hoeben, A., Lalisang, R. I., Van Helvoort, A., Wesseling, F. W. R., Hoebers, F., Baijens, L. W. J., and Schols, A. M. W. J. ( 2020) Disease‐induced and treatment‐induced alterations in body composition in locally advanced head and neck squamous cell carcinoma, Journal of Cachexia, Sarcopenia and Muscle, 11: 145– 159. https://doi.org/10.1002/jcsm.12487.

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     Article first published online:  06 November 2019

Louise Daly, Ross Dolan, Derek Power, Éadaoin Ní Bhuachalla,  Wei Sim, Marie Fallon, Samantha Cushen, Claribel Simmons, Donald C. McMillan, Barry J. Laird, Aoife Ryan

The relationship between the BMI‐adjusted weight loss grading system and quality of life in patients with incurable cancer
Background
Weight loss (WL) has long been recognized as an important factor associated with reduced quality of life (QoL) and reduced survival in patients with cancer. The body mass index (BMI)‐adjusted weight loss grading system (WLGS) has been shown to be associated with reduced survival. However, its impact on QoL has not been established. The aim of this study was to assess the relationship between this WLGS and QoL in patients with advanced cancer.
Methods
A biobank analysis was undertaken of adult patients with advanced cancer. Data collected included patient demographics, Eastern Cooperative Oncology Group performance status, and anthropometric parameters (BMI and %WL). Patients were categorized according to the BMI‐adjusted WLGS into one of five distinct WL grades (grades 0–4). QoL was collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐C30. The Kruskal–Wallis test and multivariate logistic regression analyses were used to assess the relationship between the WLGS and QoL scores. Overall survival was assessed using Kaplan–Meier curve and Cox proportional hazard models.
Results
A total of 1027 patients were assessed (51% male, median age: 66 years). Gastrointestinal cancer was most prevalent (40%), and 87% of patients had metastatic disease. Half (58%) of patients had a WL grade of 0–1, while 12%, 20%, and 10% had WL grades of 2, 3, and 4, respectively. Increasing WL grades were significantly associated with poorer QoL functioning and symptoms scales (all P < 0.05). Physical, role, and emotional functioning decreased by a median of >20 points between WL grade 0 and WL grade 4, while appetite loss, pain, dyspnoea, and fatigue increased by a median score >20 points, indicative of a large clinical significant difference. Increasing WL grades were associated with deteriorating QoL summary score. WL grades 2, 3, and 4 were independently associated with a QoL summary score below the median (<77.7) [odds ratio (OR) 1.69, P = 0.034; OR 2.06, P = 0.001; OR 4.29, P < 0.001, respectively]. WL grades 3 and 4 were independently associated with reduced overall survival [hazard ratio 1.54 (95% confidence interval: 1.22–1.93), P < 0.001 and hazard ratio 1.87 (95% confidence interval: 1.42–2.45), P < 0.001, respectively].
Conclusions
Our findings support that the WLGS is useful in identifying patients at risk of poor QoL that deteriorates with increasing WL grades. WL grade 4 is independently associated with a particularly worse prognosis and increased symptom burden. Identification and early referral to palliative care services may benefit these patients.

Daly, L., Dolan, R., Power, D., Ní Bhuachalla, É., Sim, W., Fallon, M., Cushen, S., Simmons, C., McMillan, D. C., Laird, B. J., and Ryan, A. ( 2020) The relationship between the BMI‐adjusted weight loss grading system and quality of life in patients with incurable cancer, Journal of Cachexia, Sarcopenia and Muscle, 11: 160– 168. https://doi.org/10.1002/jcsm.12499.

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     Article first published online:  24 October 2019

Maria Carmela Filomena, Daniel L. Yamamoto, Marco Caremani, Vinay K. Kadarla, Giuseppina Mastrototaro, Simone Serio, Anupama Vydyanath, Margherita Mutarelli, Arcamaria Garofalo, Irene Pertici, Ralph Knöll, Vincenzo Nigro, Pradeep K. Luther, Richard L. Lieber, Moriah R. Beck, Marco Linari, Marie‐Louise Bang

Myopalladin promotes muscle growth through modulation of the serum response factor pathway
Background
Myopalladin (MYPN) is a striated muscle‐specific, immunoglobulin‐containing protein located in the Z‐line and I‐band of the sarcomere as well as the nucleus. Heterozygous MYPN gene mutations are associated with hypertrophic, dilated, and restrictive cardiomyopathy, and homozygous loss‐of‐function truncating mutations have recently been identified in patients with cap myopathy, nemaline myopathy, and congenital myopathy with hanging big toe.
Methods
Constitutive MYPN knockout (MKO) mice were generated, and the role of MYPN in skeletal muscle was studied through molecular, cellular, biochemical, structural, biomechanical, and physiological studies in vivo and in vitro.
Results
MKO mice were 13% smaller compared with wild‐type controls and exhibited a 48% reduction in myofibre cross‐sectional area (CSA) and significantly increased fibre number. Similarly, reduced myotube width was observed in MKO primary myoblast cultures. Biomechanical studies showed reduced isometric force and power output in MKO mice as a result of the reduced CSA, whereas the force developed by each myosin molecular motor was unaffected. While the performance by treadmill running was similar in MKO and wild‐type mice, MKO mice showed progressively decreased exercise capability, Z‐line damage, and signs of muscle regeneration following consecutive days of downhill running. Additionally, MKO muscle exhibited progressive Z‐line widening starting from 8 months of age. RNA‐sequencing analysis revealed down‐regulation of serum response factor (SRF)‐target genes in muscles from postnatal MKO mice, important for muscle growth and differentiation. The SRF pathway is regulated by actin dynamics as binding of globular actin to the SRF‐cofactor myocardin‐related transcription factor A (MRTF‐A) prevents its translocation to the nucleus where it binds and activates SRF. MYPN was found to bind and bundle filamentous actin as well as interact with MRTF‐A. In particular, while MYPN reduced actin polymerization, it strongly inhibited actin depolymerization and consequently increased MRTF‐A‐mediated activation of SRF signalling in myogenic cells. Reduced myotube width in MKO primary myoblast cultures was rescued by transduction with constitutive active SRF, demonstrating that MYPN promotes skeletal muscle growth through activation of the SRF pathway.
Conclusions
Myopalladin plays a critical role in the control of skeletal muscle growth through its effect on actin dynamics and consequently the SRF pathway. In addition, MYPN is important for the maintenance of Z‐line integrity during exercise and aging. These results suggest that muscle weakness in patients with biallelic MYPN mutations may be associated with reduced myofibre CSA and SRF signalling and that the disease phenotype may be aggravated by exercise.

Filomena, M. C., Yamamoto, D. L., Caremani, M., Kadarla, V. K., Mastrototaro, G., Serio, S., Vydyanath, A., Mutarelli, M., Garofalo, A., Pertici, I., Knöll, R., Nigro, V., Luther, P. K., Lieber, R. L., Beck, M. R., Linari, M., and Bang, M.‐L. ( 2020) Myopalladin promotes muscle growth through modulation of the serum response factor pathway, Journal of Cachexia, Sarcopenia and Muscle, 11: 169– 194. https://doi.org/10.1002/jcsm.12486.

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     Article first published online:  24 October 2019

Kristine Pettersen, Sonja Andersen, Anna van der Veen, Unni Nonstad, Shinji Hatakeyama, Christian Lambert, Estelle Lach‐Trifilieff, Siver Moestue, Jana Kim, Bjørn Henning Grønberg, Alain Schilb, Carsten Jacobi, Geir Bjørkø

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia
Background
The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development.
Methods
We investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice.
Results
We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005).
Conclusions
Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

Pettersen, K., Andersen, S., van der Veen, A., Nonstad, U., Hatakeyama, S., Lambert, C., Lach‐Trifilieff, E., Moestue, S., Kim, J., Grønberg, B. H., Schilb, A., Jacobi, C., and Bjørkøy, G. ( 2020) Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia, Journal of Cachexia, Sarcopenia and Muscle, 11: 195– 207. https://doi.org/10.1002/jcsm.12489.

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     Article first published online:  25 October 2019

Martina Baraldo, Alessia Geremia, Marco Pirazzini, Leonardo Nogara, Francesca Solagna, Clara Türk, Hendrik Nolte, Vanina Romanello, Aram Megighian, Simona Boncompagni, Marcus Kruger, Marco Sandri, Bert Blaauw

Skeletal muscle mTORC1 regulates neuromuscular junction stability

Background
Skeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of mTORC1 signalling in adult skeletal muscle homeostasis is still not well defined.
Methods
Inducible, muscle‐specific Raptor and mTOR k.o. mice were generated. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force.
Results
We found no change in muscle size or contractile properties 1 month after deletion. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by weakness, muscle regeneration, mitochondrial dysfunction, and autophagy impairment. Unexpectedly, reduced mTOR signalling in muscle fibres is accompanied by the appearance of markers of fibre denervation, like the increased expression of the neural cell adhesion molecule (NCAM). Both muscle‐specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce 3–8% of NCAM‐positive fibres (P < 0.01), muscle fibrillation, and neuromuscular junction (NMJ) fragmentation in 24% of examined fibres (P < 0.001). Mechanistically, reactivation of autophagy with the small peptide Tat‐beclin1 is sufficient to prevent mitochondrial dysfunction and the appearance of NCAM‐positive fibres in Raptor k.o. muscles.
Conclusions
Our study shows that mTOR signalling in skeletal muscle fibres is critical for maintaining proper fibre innervation, preserving the NMJ structure in both the muscle fibre and the motor neuron. In addition, considering the beneficial effects of exercise in most pathologies affecting the NMJ, our findings suggest that part of these beneficial effects of exercise are through the well‐established activation of mTORC1 in skeletal muscle during and after exercise.

Baraldo, M., Geremia, A., Pirazzini, M., Nogara, L., Solagna, F., Türk, C., Nolte, H., Romanello, V., Megighian, A., Boncompagni, S., Kruger, M., Sandri, M., and Blaauw, B. ( 2020) Skeletal muscle mTORC1 regulates neuromuscular junction stability, Journal of Cachexia, Sarcopenia and Muscle, 11, 208– 225. https://doi.org/10.1002/jcsm.12496.

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     Article first published online:  13 November 2019

Thomas Kunzke, Achim Buck, Verena M. Prade, Annette Feuchtinger, Olga Prokopchuk, Marc E. Martignoni, Simone Heisz, Hans Hauner, Klaus‐Peter Janssen, Axel Walch, Michaela Aichler

Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction
Background
Cachexia is the direct cause of at least 20% of cancer‐associated deaths. Muscle wasting in skeletal muscle results in weakness, immobility, and death secondary to impaired respiratory muscle function. Muscle proteins are massively degraded in cachexia; nevertheless, the molecular mechanisms related to this process are poorly understood. Previous studies have reported conflicting results regarding the amino acid abundances in cachectic skeletal muscle tissues. There is a clear need to identify the molecular processes of muscle metabolism in the context of cachexia, especially how different types of molecules are involved in the muscle wasting process.
Methods
New in situ ‐omics techniques were used to produce a more comprehensive picture of amino acid metabolism in cachectic muscles by determining the quantities of amino acids, proteins, and cellular metabolites. Using matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry imaging, we determined the in situ concentrations of amino acids and proteins, as well as energy and other cellular metabolites, in skeletal muscle tissues from genetic mouse cancer models (n = 21) and from patients with cancer (n = 6). Combined results from three individual MALDI mass spectrometry imaging methods were obtained and interpreted. Immunohistochemistry staining for mitochondrial proteins and myosin heavy chain expression, digital image analysis, and transmission electron microscopy complemented the MALDI mass spectrometry imaging results.
Results
Metabolic derangements in cachectic mouse muscle tissues were detected, with significantly increased quantities of lysine, arginine, proline, and tyrosine (P = 0.0037, P = 0.0048, P = 0.0430, and P = 0.0357, respectively) and significantly reduced quantities of glutamate and aspartate (P = 0.0008 and P = 0.0124). Human skeletal muscle tissues revealed similar tendencies. A majority of altered amino acids were released by the breakdown of proteins involved in oxidative phosphorylation. Decreased energy charge was observed in cachectic muscle tissues (P = 0.0101), which was related to the breakdown of specific proteins. Additionally, expression of the cationic amino acid transporter CAT1 was significantly decreased in the mitochondria of cachectic mouse muscles (P = 0.0133); this decrease may play an important role in the alterations of cationic amino acid metabolism and decreased quantity of glutamate observed in cachexia.
Conclusions
Our results suggest that mitochondrial dysfunction has a substantial influence on amino acid metabolism in cachectic skeletal muscles, which appears to be triggered by diminished CAT1 expression, as well as the degradation of mitochondrial proteins. These findings provide new insights into the pathobiochemistry of muscle wasting.

Kunzke, T., Buck, A., Prade, V. M., Feuchtinger, A., Prokopchuk, O., Martignoni, M. E., Heisz, S., Hauner, H., Janssen, K.‐P., Walch, A., and Aichler, M. ( 2019) Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction, Journal of Cachexia, Sarcopenia and Muscle, XXX, doi: https://doi.org/10.1002/jcsm.12498.

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     Article first published online:  31 January 2020

Yasuhiro Nishida, Allah Nawaz, Tomonobu Kado, Akiko Takikawa, Yoshiko Igarashi, Yasuhiro Onogi, Tsutomu Wada, Toshiyasu Sasaoka, Seiji Yamamoto, Masakiyo Sasahara, Johji Imura, Kumpei Tokuyama, Isao Usui, Takashi Nakagawa, Shiho Fujisaka, Yagi Kunimasa, Kazuyuki Tobe

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway
Background
Skeletal muscle is mainly responsible for insulin‐stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance.
Methods
We fed 6‐week‐old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high‐fat‐diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis.
Results
AX‐treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX‐treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic–euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA‐mediated AMPK‐depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK‐depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise‐induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue.
Conclusions
We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.

Nishida, Y., Nawaz, A., Kado, T., Takikawa, A., Igarashi, Y., Onogi, Y., Wada, T., Sasaoka, T., Yamamoto, S., Sasahara, M., Imura, J., Tokuyama, K., Usui, I., Nakagawa, T., Fujisaka, S., Kunimasa, Y., and Tobe, K. ( 2020) Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway, Journal of Cachexia, Sarcopenia and Muscle, 11: 241– 258. https://doi.org/10.1002/jcsm.12530.

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     Article first published online:  07 November

Alexander S. Ham, Kathrin Chojnowska, Lionel A. Tintignac, Shuo Lin, Alexander Schmidt, Daniel J. Ham, Michael Sinnreich, Markus A. Rüegg

mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice
Background
The balance between protein synthesis and degradation (proteostasis) is a determining factor for muscle size and function. Signalling via the mammalian target of rapamycin complex 1 (mTORC1) regulates proteostasis in skeletal muscle by affecting protein synthesis and autophagosomal protein degradation. Indeed, genetic inactivation of mTORC1 in developing and growing muscle causes atrophy resulting in a lethal myopathy. However, systemic dampening of mTORC1 signalling by its allosteric inhibitor rapamycin is beneficial at the organismal level and increases lifespan. Whether the beneficial effect of rapamycin comes at the expense of muscle mass and function is yet to be established.
Methods
We conditionally ablated the gene coding for the mTORC1‐essential component raptor in muscle fibres of adult mice [inducible raptor muscle‐specific knockout (iRAmKO)]. We performed detailed phenotypic and biochemical analyses of iRAmKO mice and compared them with muscle‐specific raptor knockout (RAmKO) mice, which lack raptor in developing muscle fibres. We also used polysome profiling and proteomics to assess protein translation and associated signalling in skeletal muscle of iRAmKO mice.
Results
Analysis at different time points reveal that, as in RAmKO mice, the proportion of oxidative fibres decreases, but slow‐type fibres increase in iRAmKO mice. Nevertheless, no significant decrease in body and muscle mass or muscle fibre area was detected up to 5 months post‐raptor depletion. Similarly, ex vivo muscle force was not significantly reduced in iRAmKO mice. Despite stable muscle size and function, inducible raptor depletion significantly reduced the expression of key components of the translation machinery and overall translation rates.
Conclusions
Raptor depletion and hence complete inhibition of mTORC1 signalling in fully grown muscle leads to metabolic and morphological changes without inducing muscle atrophy even after 5 months. Together, our data indicate that maintenance of muscle size does not require mTORC1 signalling, suggesting that rapamycin treatment is unlikely to negatively affect muscle mass and function.

Ham, A. S., Chojnowska, K., Tintignac, L. A., Lin, S., Schmidt, A., Ham, D. J., Sinnreich, M., and Rüegg, M. A. ( 2020) mTORC 1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice, Journal of Cachexia, Sarcopenia and Muscle, 11: 259– 273. https://doi.org/10.1002/jcsm.12505.

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     Article first published online:  12 February 2020

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference

Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference
This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 12th Cachexia Conference held in Berlin, Germany, in December 2019. Herein, we summarize the biological and clinical significance of different strategies including antibodies that target Fn14, Spsb 1, SAA1 treatment, ZIP14, a MuRF1 inhibitor, and new diagnostic tools like T‐cell communication targets and cut‐offs for the detection of skeletal muscle wasting. Of particular interest were the transplantation of mesenchymal stromal cells and muscle stem cell communication. Importantly, one presentation discussed the effect of metal ion transporter ZIP14 loss that reduces cancer‐induced cachexia. The potential of anti‐ZIP14 antibodies and zinc chelation as anti‐cachexia therapy may require testing in patients with cancer cachexia. Large clinical studies were presented such as RePOWER (observational study of patients with primary mitochondrial myopathy), MMPOWER (treatment with elamipretide in patients with primary mitochondrial myopathy), and ACT‐ONE as well as new mouse models like the KPP mouse. Promising treatments include rapamycin analogue treatment, anamorelin, elanapril, glucocorticoids, SAA1, antibodies that target Fn14, and a MuRF1 inhibitor. Clinical studies investigated novel approaches, including the role of exercise. It remains a fact, however, that effective treatments for cachexia and wasting disorders are urgently needed in order to improve patients' quality of life and their survival.

Ebner, N., Anker, S. D., and von Haehling, S. ( 2020) Recent developments in the field of cachexia, sarcopenia, and muscle wasting: highlights from the 12th Cachexia Conference, Journal of Cachexia, Sarcopenia and Muscle, 11: 274– 285. https://doi.org/10.1002/jcsm.12552.

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     Article first published online:  12 February 2020

Abstract

(2020), Abstract. Journal of Cachexia, Sarcopenia and Muscle, 11: 286-329. doi:10.1002/jcsm.12551

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     Article first published online:  03 January 2020

Xiao‐Ming Zhang, Andy S.K. Chen,g Qingli Dou, Wenwu Zhang, Yingchun Zeng 

Comment on: “Sarcopenia and its association with falls and fractures in older adults: A systematic review and meta‐analysis” by Yeung et al.

Zhang, X.‐M., Cheng, A. S. K., Dou, Q., Zhang, W., and Zeng, Y. ( 2020) Comment on: “Sarcopenia and its association with falls and fractures in older adults: A systematic review and meta‐analysis” by Yeung et al, Journal of Cachexia, Sarcopenia and Muscle, 11: 330– 331. https://doi.org/10.1002/jcsm.12467.

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     Article first published online:  05 January 2020

Suey S.Y. Yeung, Martijn W. Heymans, Andrea B. Maier

The authors reply: Letter on: “ Sarcopenia and its association with falls and fracturesin older adults: A systematic review andmeta‐analysis” by Zhang et

Yeung, S. S. Y., Heymans, M. W., and Maier, A. B. ( 2020) The authors reply: Letter on: “ Sarcopenia and its association with falls and fracturesin older adults: A systematic review andmeta‐analysis” by Zhang et al, Journal of Cachexia, Sarcopenia and Muscle, 11: 332– 335. https://doi.org/10.1002/jcsm.12521.

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     Article first published online:  15 July 2019

Yeshun Wu, Bin Zhu, Zijun Chen, Jiahao Duan, Ling Yang

Comment on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al.

Wu, Y., Zhu, B., Chen, Z., Duan, J., and Yang, L. ( 2020) Comment on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al, Journal of Cachexia, Sarcopenia and Muscle, 11: 336– 337. https://doi.org/10.1002/jcsm.12465.

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     Article first published online:  06 November 2019

Lynette J. Oost, Marco Sandri

The authors reply: Letter on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al.

Oost, L. J., Sandri, M., and Romanello, V. ( 2020) The authors reply: Letter on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al, Journal of Cachexia, Sarcopenia and Muscle, 11: 338– 340. https://doi.org/10.1002/jcsm.12500.

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