Journal of Cachexia Sarcopenia and Muscle

Journal of Cachexia Sarcopenia and Muscle

Relationship between pulmonary function and physical performance among community‐living people: results from Look‐up 7+ study

04-12-2019 – Francesco Landi, Sara Salini, Maria Beatrice Zazzara, Anna Maria Martone, Sofia Fabrizi, Mariangela Bianchi, Matteo Tosato, Anna Picca, Riccardo Calvani, Emanuele Marzetti

Abstract
Background
While respiratory muscle strength is recognized to decline with aging process, the relationship between sarcopenia and pulmonary function remains to be studied. The present study was undertaken to provide a better insight into the comprehension of the relationship between pulmonary function and muscle function (strength and physical performance) using an unselected sample of subjects assessed during the Longevity Check‐up 7+ project.
Methods
Look‐up 7+ is an ongoing cross‐sectional survey started in June 2015 and conducted in unconventional settings (i.e. exhibitions, malls, and health promotion campaigns) across Italy. Candidate participants are eligible for enrolment if they are at least 18 years of age and provide written informed consent. Muscle strength was assessed by handgrip strength test, and physical performance was evaluated by chair stand test. Spirometer analysis was performed using the Air
Smart system, and the largest forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and peak expiratory flow (PEF) values were collected.
Results
The mean age of 925 subjects participating in the Longevity check‐7+ surveys and receiving the spirometer evaluation was 55.6 years (range from 18 to 98 years), and 501 (54%) were women. Overall, both in male and female participants, FVC, FEV1 and PEF positively correlated with handgrip strength and chair stand tests. The receiver operator characteristic curve analysis revealed that the areas under the curves for FVC, FEV1, and PEF were 0.79, 0.80 and 0.80, respectively.
Conclusions
The results clearly show that pulmonary function was positively associated with handgrip strength and chair stand tests. Based on this observation, muscle strength, physical performance, and pulmonary function should be recommended as the method of choice for the early detection of individuals at risk of probable sarcopenia and at the same time to better characterized the severity of sarcopenia status.

Muscle mass, strength, and physical performance predicting activities of daily living: a meta‐analysis

01-12-2019 – Daniel X.M. Wang, Jessica Yao, Yasar Zirek, Esmee M. Reijnierse, Andrea B. Maier

Journal Article, Review

Abstract
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.

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

19-11-2019 – 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. Almeida, Patricia C. Brum, Edilamar M. Oliveira, Ludhmila Hajjar, Roberto Kalil Filho, Carlos Eduardo Negrão

Journal Article

Abstract
Background
The exercise intolerance in chronic heart failure with reduced ejection fraction (HFr
EF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFr
EF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle micro
RNA‐1 expression and downstream‐associated pathways in patients with HFr
EF 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 micro
RNA‐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 Myo
D 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 micro
RNA‐1 and percent changes in follistatin m
RNA (P = 0.001, rho = 0.58) and between percent changes in follistatin m
RNA and percent changes in peak VO2 (P = 0.004, rho = 0.51).
Conclusions
AET upregulates micro
RNA‐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 micro
RNA‐1 also decreased HDAC4 and increased MEF2c, Myo
D, 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 HFr
EF. IMT caused no changes in micro
RNA‐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.
Clinical
Trials.gov (Identifier: NCT01747395)

Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction

13-11-2019 – 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

Abstract
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.

Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis‐associated cachexia

13-11-2019 – 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

Journal Article

Abstract
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 Myo
D) 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.

mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice

07-11-2019 – Alexander S. Ham, Kathrin Chojnowska, Lionel A. Tintignac, Shuo Lin, Alexander Schmidt, Daniel J. Ham, Michael Sinnreich, Markus A. Rüegg

Journal Article

Abstract
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 (m
TORC1) regulates proteostasis in skeletal muscle by affecting protein synthesis and autophagosomal protein degradation. Indeed, genetic inactivation of m
TORC1 in developing and growing muscle causes atrophy resulting in a lethal myopathy. However, systemic dampening of m
TORC1 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 m
TORC1‐essential component raptor in muscle fibres of adult mice inducible raptor muscle‐specific knockout (i
RAm
KO). We performed detailed phenotypic and biochemical analyses of i
RAm
KO mice and compared them with muscle‐specific raptor knockout (RAm
KO) 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 i
RAm
KO mice.
Results
Analysis at different time points reveal that, as in RAm
KO mice, the proportion of oxidative fibres decreases, but slow‐type fibres increase in i
RAm
KO 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 i
RAm
KO 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 m
TORC1 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 m
TORC1 signalling, suggesting that rapamycin treatment is unlikely to negatively affect muscle mass and function.

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

06-11-2019 – Lynette J. Oost, Marco Sandri, Vanina Romanello

Letter

The relationship between the BMI‐adjusted weight loss grading system and quality of life in patients with incurable cancer

06-11-2019 – 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

Journal Article

Abstract
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.

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

30-10-2019 – Mauro Monforte, Francesco Laschena, Pierfrancesco Ottaviani, Maria Rosaria Bagnato, Anna Pichiecchio, Giorgio Tasca, Enzo Ricci

Journal Article

Abstract
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.

CT‐measured skeletal muscle mass used to assess frailty in patients with head and neck cancer

29-10-2019 – Aniek T. Zwart, Anouk Hoorn, Peter M.A. Ooijen, Roel J.H.M. Steenbakkers, Geertruida H. Bock, Gyorgy B. Halmos

Journal Article

Abstract
Background
Skeletal muscle depletion or sarcopenia is related to multiple adverse clinical outcome. However, frailty questionnaires are currently applied in the daily practice to identify patients who are potentially (un)suitable for treatment but are time consuming and straining for patients and the clinician. Screening for sarcopenia in patients with head and neck cancer (HNC) could be a promising fast biomarker for frailty. Our objective was to quantify sarcopenia with pre‐treatment low skeletal muscle mass from routinely obtained neck computed tomography scans at level of third cervical vertebra in patients diagnosed with HNC and evaluate its association with frailty.
Methods
A total of 112 HNC patients with Stages III and IV disease were included from a prospective databiobank. The amount of skeletal muscle mass was retrospectively defined using the skeletal muscle index (SMI). Correlation analysis between SMI and continuous frailty data and the observer agreement were analysed with Pearsons r correlation coefficients. Sarcopenia was present when SMI felt below previously published non‐gender specific thresholds (<43.2 cm2/m2). Frailty was evaluated by Geriatrics 8 (G8), Groningen Frailty Indicator, Timed Up and Go test, and Malnutrition Universal Screening Tool. A univariate and multivariate logistic regression analysis was performed for all patients and men separately to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs).
Results
The cohort included 82 men (73%) and 30 women (27%), with a total mean age of 63 (±9) years. The observer agreement for cross‐sectional measurements was excellent for both intra‐observer variability (r = 0.99, P < 0.001) and inter‐observer variability (r = 0.98, P < 0.001). SMI correlated best with G8 frailty score (r = 0.38, P < 0.001) and did not differ per gender. Sarcopenia was present in 54 (48%) patients, whereof 25 (46%) men and 29 (54%) women. Prevalence of frailty was between 5% and 54% depending on the used screening tool. The multivariate regression analysis for all patients and men separately isolated the G8 questionnaire as the only independent variable associated with sarcopenia (OR 0.76, 95% CI 0.66–0.89, P < 0.001 and OR 0.76, 95% CI 0.66–0.88, P < 0.001, respectively).
Conclusions
This is the first study that demonstrates that sarcopenia is independently associated with frailty based on the G8 questionnaire in HNC patients. These results suggest that in the future, screening for sarcopenia on routinely obtained neck computed tomography scans may replace time consuming frailty questionnaires and help to select the (un)suitable patients for therapy, which is highly clinically relevant.

Associations between sleep conditions and body composition states: results of the EPISONO study

29-10-2019 – “Ronaldo D. Piovezan, Camila Hirotsu, Renato Moizinho, Helton Sá Souza, Vania DAlmeida, Sergio Tufik, Dalva Poyares”

Journal Article

Abstract
Background
Evidence suggests anthropometric indicators of obesity are associated with changes in sleep quality and quantity, and the presence of obstructive sleep apnoea (OSA). Investigations including diverse and objective evaluations of sleep and body composition are scarce. We aimed to evaluate the associations between indicators of sleep impairment and body composition states in a sample from a population‐based study.
Methods
Participants of the first follow‐up of the EPISONO (São Paulo, Brazil) >50 years were cross‐sectionally evaluated. Sleep was assessed through questionnaires, actigraphy, and polysomnography. Body composition was evaluated by bioelectrical impedance analysis. Appendicular skeletal muscle mass adjusted for body mass index defined sarcopenia (men <0.789 and women <0.512). Total body fat defined obesity (men >30% and women >40%). The overlap between both conditions defined sarcopenic obesity (SO). Final results were obtained by multinomial logistic regression analysis.
Results
Three hundred fifty‐nine adults mean (standard deviation) age, 61 (8.8) years; 212 (59.1%) female were enrolled. Obesity was detected in 22.6% of the sample, sarcopenia in 5.6%, and SO in 16.2%. After controlling for covariates, OSA was associated with SO odds ratio = 3.14, 95% confidence interval (CI) = 1.49–6.61. Additionally, nocturnal hypoxaemia was associated with both obesity (adjusted odds ratio = 2.59, 95% CI = 1.49–4.49) and SO (odds ratio = 2.92, 95% CI = 1.39–6.13). Other indicators of poor sleep/sleep disorders were not associated with body composition states.
Conclusions
Sarcopenic obesity but not obesity alone was associated with OSA. Both obesity and SO but not sarcopenia were associated with nocturnal hypoxaemia. The findings suggest a complex pathophysiologic relationship between adverse body composition states and OSA. Upcoming research on risk factors and therapeutic interventions for OSA should target synchronically the lean and adipose body tissues.

Sarcopenia: A Time for Action. An SCWD Position Paper

29-10-2019 – Juergen Bauer, John E. Morley, Annemie M.W.J. Schols, Luigi Ferrucci, Alfonso J. Cruz‐Jentoft, Elsa Dent, Vickie E. Baracos, Jeffrey A. Crawford, Wolfram Doehner, Steven B. Heymsfield, Aminah Jatoi, Kamyar Kalantar‐Zadeh, Mitja Lainscak, Francesco Landi, Alessandro Laviano, Michelangelo Mancuso, Maurizio Muscaritoli, Carla M. Prado, Florian Strasser, Stephan Haehling, Andrew J.S. Coats, Stefan D. Anker

Journal Article

Abstract
The term sarcopenia was introduced in 1988. The original definition was a “muscle loss” of the appendicular muscle mass in the older people as measured by dual energy x‐ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC‐F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease‐related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age‐related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age‐related and disease‐related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life‐long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.

Gait speed as a mediator of the effect of sarcopenia on dependency in activities of daily living

29-10-2019 – Miguel A. Perez‐Sousa, Luis Carlos Venegas‐Sanabria, Diego Andrés Chavarro‐Carvajal, Carlos Alberto Cano‐Gutierrez, Mikel Izquierdo, Jorge Enrique Correa‐Bautista, Robinson Ramírez‐Vélez

Journal Article

Abstract
Background
Sarcopenia in older adults is strongly associated with an increase in dependency in activities of daily living (ADL) and with a decline in gait speed. Interestingly, gait speed has been shown to independently predict mortality. In this context, our study aimed to explore the mediator role of gait speed on the relationship between sarcopenia and dependency in ADL.
Methods
A cross‐sectional study was conducted in Colombia, 19 705 older adults with a mean age of 70 years, 55.6% women, 16.1% with sarcopenia, and 14.7% mild, moderate, or severe dependency in ADL, according to ‘SABE Survey 2015’. Sarcopenia was assessed by calf circumference and ADL dependence through the Barthel Index. Gait speed was measured over a distance of 3 m. The association between sarcopenia condition and gait speed and dependency level was analysed by linear regression adjusted by covariates. To examine whether gait speed mediated the association between sarcopenia and dependence components of physical function, simple mediation models were generated using ordinary least squares with the macro PROCESS version 3.2, adjusted for age, sex, and body mass index (BMI).
Results
Significant differences (P < 0.05) were found in gait speed and dependency in ADL between the sarcopenia and non‐sarcopenia groups after adjusting for age, sex, and BMI. BMI was significantly higher in the non‐sarcopenia group whereas dependency was significantly higher in the sarcopenia group (19.6% vs. 13.8%). Results from mediation model regression analysis indicated a significant and direct detrimental effect of sarcopenia on dependency in ADL (β = −0.05; P < 0.001), and a significant indirect effect of gait speed on the direct effect (−0.009 to −0.004).
Conclusions
The negative effect of sarcopenia on functional dependence was mediated by the gait speed. Therefore, gait speed may positively influence the detrimental effect of sarcopenia for dependency, after adjusting for age, gender, and BMI. Consequently, physical exercise should be promoted and focused to circumvent the gait speed decline associated with age in older people with sarcopenia.

The clinical relevance of adiposity when assessing muscle health in men treated with androgen deprivation for prostate cancer

29-10-2019 – Patrick J. Owen, Robin M. Daly, Jack Dalla Via, Niamh L. Mundell, Patricia M. Livingston, Timo Rantalainen, Steve F. Fraser

Journal Article

Abstract
Background
Androgen deprivation therapy (ADT) for prostate cancer (PCa) may prospectively decrease absolute lean mass (LM) and increase absolute fat mass (FM). Given that estimates of LM by dual‐energy X‐ray absorptiometry may be overestimated in obese people, this study examined the influence of adiposity on muscle health in men treated with ADT for PCa.
Methods
This cross‐sectional study examined the influence of adiposity on total and appendicular LM (ALM), muscle cross‐sectional (CSA), and muscle strength in 70 men treated with ADT mean (standard deviation) age, 71 (6) years for PCa compared with age‐matched PCa (n = 52) and healthy controls (n = 70). Total body LM, FM and ALM, and 66% tibia and radius muscle CSA were quantified by dual‐energy X‐ray absorptiometry and peripheral quantitative computed tomography, respectively. ALM was further divided by height (m2) or body mass index, with muscle CSA expressed as a per cent of total limb CSA. Upper and lower body and back (three‐repetition maximum and dynamometry) muscle strength were expressed per kilogram of body weight.
Results
On average, ADT‐treated men had 4.4–6.4 kg greater FM compared with controls (P ≤ 0.014) and there were no differences in total body or ALM. Total body per cent LM and ALMBMI were 3.8–5.4% (P ≤ 0.001) and 7.8–9.4% (P ≤ 0.001) lower, respectively, in ADT‐treated men compared with both controls. Percentage muscle CSA at both sites and muscle strength (except leg) were 3.0–6.0% (P ≤ 0.031) and 15–17% (P ≤ 0.010) lower, respectively, in ADT‐treated men compared with both controls.
Conclusions
The findings from this study indicate muscle mass, size, and strength are compromised in men treated with ADT after accounting for their increased adiposity or body size.

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

29-10-2019 – Joanna D.C.C. Lima, Estefania Simoes, Gabriela Castro, Mychel Raony P.T. Morais, Emidio M. Matos‐Neto, Michele J. Alves, Nelson I. Pinto, Raquel G. Figueredo, Telma M.T. Zorn, Aloísio S. Felipe‐Silva, Flavio Tokeshi, José P. Otoch, Paulo Alcantara, Fernanda J. Cabral, Emer S. Ferro, Alessandro Laviano, Marilia Seelaender

Journal Article

Abstract
Background
Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro‐environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro‐environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients.
Methods74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components.
Results
Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte–macrophage colony‐stimulating factor, interferon‐α, and interleukin (IL)‐8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight‐stable counterparts. Also, IL‐8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α‐smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)‐β1, TGF‐β2, and TGF‐β3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen‐activated protein kinase alteration. Hypoxia‐inducible factor‐1α m
RNA content was significantly increased in the tumour of cachectic patients, when compared with weight‐stable group (P = 0.005).
Conclusions
Our results demonstrate TGF‐β pathway activation in the tumour in cachexia, through the (non‐canonical) mitogen‐activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF‐β‐induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.

Association of lifestyle factors and inflammation with sarcopenic obesity: data from the PREDIMED‐Plus trial

29-10-2019 – Itziar Abete, Jadwiga Konieczna, M. Angeles Zulet, Aina M. Galmés‐Panades, Idoia Ibero‐Baraibar, Nancy Babio, Ramón Estruch, Josep Vidal, Estefanía Toledo, Cristina Razquin, Rafael Bartolomé, Andrés Díaz‐Lopez, Miquel Fiol, Rosa Casas, Josep Vera, Pilar Buil‐Cosiales, Xavier Pintó, Emili Corbella, Maria Puy Portillo, Jose Antonio Paz, Vicente Martín, Lidia Daimiel, Albert Goday, Nuria Rosique‐Esteban, Jordi Salas‐Salvadó, Dora Romaguera, J. Alfredo Martínez, on behalf of PREDIMED‐PLUS Investigators

Journal Article

Abstract
Background
Sarcopenia is a progressive age‐related skeletal muscle disorder associated with increased likelihood of adverse outcomes. Muscle wasting is often accompanied by an increase in body fat, leading to ‘sarcopenic obesity’. The aim of the present study was to analyse the association of lifestyle variables such as diet, dietary components, physical activity (PA), body composition, and inflammatory markers, with the risk of sarcopenic obesity.
Methods
A cross‐sectional analysis based on baseline data from the PREDIMED‐Plus study was performed. A total of 1535 participants (48% women) with overweight/obesity (body mass index: 32.5 ± 3.3 kg/m2; age: 65.2 ± 4.9 years old) and metabolic syndrome were categorized according to sex‐specific tertiles (T) of the sarcopenic index (SI) as assessed by dual‐energy X‐ray absorptiometry scanning. Anthropometrical measurements, biochemical markers, dietary intake, and PA information were collected. Linear regression analyses were carried out to evaluate the association between variables.
Results
Subjects in the first SI tertile were older, less physically active, showed higher frequency of abdominal obesity and diabetes, and consumed higher saturated fat and less vitamin C than subjects from the other two tertiles (all P < 0.05). Multiple adjusted linear regression models evidenced significant positive associations across tertiles of SI with adherence to the Mediterranean dietary score (P‐trend < 0.05), PA (P‐trend < 0.0001), and the 30 s chair stand test (P‐trend < 0.0001), whereas significant negative associations were found with an inadequate vitamin C consumption (P‐trend < 0.05), visceral fat and leucocyte count (all P‐trend < 0.0001), and some white cell subtypes (neutrophils and monocytes), neutrophil‐to‐lymphocyte ratio, and platelet count (all P‐trend < 0.05). When models were additionally adjusted by potential mediators (inflammatory markers, diabetes, and waist circumference), no relevant changes were observed, only dietary variables lost significance.
Conclusions
Diet and PA are important regulatory mediators of systemic inflammation, which is directly involved in the sarcopenic process. A healthy dietary pattern combined with exercise is a promising strategy to limit age‐related sarcopenia.

Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

29-10-2019 – Volker Adams, T. Scott Bowen, Sarah Werner, Peggy Barthel, Christina Amberger, Anne Konzer, Johannes Graumann, Peter Sehr, Joe Lewis, Jan Provaznik, Vladimir Benes, Petra Büttner, Alexander Gasch, Norman Mangner, Christian C. Witt, Dittmar Labeit, Axel Linke, Siegfried Labeit

Journal Article

Abstract
Background
Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small‐molecule inhibitor of Mu
RF1 in treating CHF‐induced diaphragm myopathy and loss of contractile function.
Methods
Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham‐operated animals (sham) served as controls. One week post‐left anterior descending coronary artery ligation animals were randomized into two groups—one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946—a recently described Mu
RF1‐interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed.
Results
Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up‐regulation of the Mu
RF1 and Mu
RF2 was attenuated after infarct.
Conclusions
Our murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting Mu
RF1/Mu
RF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.

Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa

29-10-2019 – Raquel G.F. Costa, Paula L. Caro, Emídio M. Matos‐Neto, Joanna D.C.C. Lima, Katrin Radloff, Michele J. Alves, Rodolfo G. Camargo, Ana Flávia M. Pessoa, Estefania Simoes, Patrícia Gama, Denise C. Cara, Aloísio S.F. Silva, Welbert O. Pereira, Linda F. Maximiano, Paulo S.M. Alcântara, José P. Otoch, Giorgio Trinchieri, Alessandro Laviano, Maurizio Muscaritoli, Marília Seelaender

Journal Article

Abstract
Background
Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia‐related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour.
Methods
Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex® x
MAP) analyses.
Results
There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL‐6) and IL‐8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL‐7, IL‐13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte‐colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL‐13 and transforming growth factor beta 3.
Conclusions
The changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome.

The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

29-10-2019 – Xiaoling Zhong, Marianne Pons, Christophe Poirier, Yanlin Jiang, Jianguo Liu, George E. Sandusky, Safi Shahda, Attila Nakeeb, C. Max Schmidt, Michael G. House, Eugene P. Ceppa, Nicholas J. Zyromski, Yunlong Liu, Guanglong Jiang, Marion E. Couch, Leonidas G. Koniaris, Teresa A. Zimmers

Journal Article

Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice.
Methods
Isoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes.
Results
Murine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not.
Conclusions
Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

Physical function‐derived cut‐points for the diagnosis of sarcopenia and dynapenia from the Canadian longitudinal study on aging

29-10-2019 – Anne‐Julie Tessier, Simon S. Wing, Elham Rahme, José A. Morais, Stéphanie Chevalier

Journal Article

Abstract
Background
Aging is associated with sarcopenia (low muscle mass) and dynapenia (low muscle strength) leading to disability and mortality. Widely used previous cut‐points for sarcopenia were established from dated, small, or pooled cohorts. We aimed to identify cut‐points of low strength as a determinant of impaired physical performance and cut‐points of low appendicular lean mass (ALM) as a predictor of low strength in a single, large, and contemporary cohort of community‐dwelling older adults and compare these criteria with others.
Methods
Cross‐sectional analyses were conducted on baseline data from 4725 and 4363 community‐dwelling men and women (65–86 years, 96.8% Caucasian) of the Canadian longitudinal study on aging comprehensive cohort. Physical performance was evaluated from gait speed, timed up‐and‐go, chair rise, and balance tests; a weighted‐sum score was computed using factor analysis. Strength was measured by handgrip dynamometry; ALM, by dual‐energy X‐ray absorptiometry and ALM index (ALMI; kg/m2), was calculated. Classification and regression tree analyses determined optimal sex‐specific cut‐points of ALMI predicting low strength and of strength predicting impaired physical performance (score < 1.5 SD below the sex‐specific mean).
Results
Modest associations were found between ALMI and strength and between strength and physical performance score in both sexes. ALMI was not an independent predictor of physical performance score. Cut‐points of <33.1 and <20.4 kg were found to define dynapenia in men and in women, respectively, corresponding to 21.5% and 24.0% prevalence rates. Sarcopenia cut‐points were <7.76 kg/m2 in men and <5.72 kg/m2 in women; prevalence rates of 21.7% and 13.7%. Overall, 8.3% of men and 5.5% of women had sarco‐dynapenia. Sarcopenic were older and had lower fat mass and body mass index (BMI) than non‐sarcopenic participants. While the agreement between current criteria and the updated European Working Group for Sarcopenia in Older Persons recommendations was fair, we found only slight agreement with the Foundation for the National Institute of Health sarcopenia project. Older persons identified with sarcopenia as per the Foundation for the National Institute of Health criteria (using ALM/BMI as the index) have higher BMI and fat mass compared with non‐sarcopenic and have normal ALMI as per our criteria.
Conclusions
The proposed function‐derived cut‐points established from this single, large, and contemporary Canadian cohort should be used for the identification of sarcopenia and dynapenia in Caucasian older adults. We advise on using criteria based on ALMI in the diagnosis of sarcopenia. The modest agreement between sarcopenia and dynapenia denotes potential distinct health implications justifying to study both components separately.

Macrophages protect against loss of adipose tissue during cancer cachexia

29-10-2019 – Merve Erdem, Diana Möckel, Sandra Jumpertz, Cathleen John, Athanassios Fragoulis, Ines Rudolph, Johanna Wulfmeier, Jochen Springer, Henrike Horn, Marco Koch, Georg Lurje, Twan Lammers, Steven Olde Damink, Gregory Kroft, Felix Gremse, Thorsten Cramer

Journal Article

Abstract
Background
Cancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia; however, clinical studies with anti‐inflammatory drugs failed to show distinct cachexia‐inhibiting effects. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)‐associated cachexia.
Methods
A transgenic HCC mouse model was intercrossed with mice harbouring a defect in myeloid cell‐mediated inflammation. Body composition of mice was analysed via nuclear magnetic resonance spectroscopy and microcomputed tomography. Quantitative PCR was used to determine adipose tissue browning and polarization of adipose tissue macrophages. The activation state of distinct areas of the hypothalamus was analysed via immunofluorescence. Multispectral immunofluorescence imaging and immunoblot were applied to characterize sympathetic neurons and macrophages in visceral adipose tissue. Quantification of pro‐inflammatory cytokines in mouse serum was performed with a multiplex immunoassay. Visceral adipose tissue of HCC patients was quantified via the L3 index of computed tomography scans obtained during routine clinical care.
Results
We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography‐based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell‐mediated inflammation defect resulted in reduced expression of pro‐inflammatory cytokines in the serum of HCC‐bearing mice, this unexpectedly did not translate into diminished but rather enhanced cachexia‐associated fat loss. Defective myeloid cell‐mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer‐induced fat loss.
Conclusions
Myeloid cell‐mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer‐induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti‐inflammatory drugs.

Rapid atrophy of cardiac left ventricular mass in patients with non‐small cell carcinoma of the lung

29-10-2019 – Seyyed Mohammad Reza Kazemi‐Bajestani, Harald Becher, Charles Butts, Naveen S. Basappa, Michael Smylie, Anil Abraham Joy, Randeep Sangha, Andrea Gallivan, Peter Kavsak, Quincy Chu, Vickie E. Baracos

Journal Article

Abstract
Background
Cancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac function, symptoms, and clinical outcomes.
Methods
Treatment naïve metastatic non‐small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin‐based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function LV ejection fraction, global longitudinal strain (GLS), diastolic function, computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival.
Results
During 112 ± 6 days, the median change in LVM was −8.9% 95% confidence interval (95% CI) −10.8 to −4.8, P < 0.001. Quartiles of LVM loss were −20.1%, −12.9%, −4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle odds ratio (OR) = 4.5, 95% CI: 1.4–14.8, P=0.01 and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7–36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9–22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C‐reactive protein (P=0.008), high sensitivity troponin T (hs‐Tn
T) (P=0.03), and galectin‐3 (P=0.02) increased over time, while N‐terminal pro B‐type natriuretic peptide and hs‐c
Tn
I did not change over time. C‐reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2–46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4–153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9–22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4–35.8, P<0.001), and deterioration of performance status (OR = 4.8, 95% CI: 1.3–18.3,P=0.02). Patients with concurrent loss of LVM, skeletal muscle, and fat were more likely to deteriorate in all three symptom domains and to have reduced survival (P=0.05).
Conclusions
Intense LVM atrophy is associated with non‐small cell lung cancer‐induced cachexia. Loss of LVM was associated with emerging alterations of GLS, indicating subtle changes in left ventricular function. Longer term studies are needed to assess the full scope of cardiac atrophy and its impact. LVM atrophy arises in conjunction with losses of fat and skeletal muscle and is temporally associated with meaningful declines in performance status, worsening of fatigue, and dyspnoea, as well as poorer tumour response and decreased survival. The specific contribution of LVM atrophy to these outcomes requires further study.

Changes in knee extension peak torque and body composition and their relationship with change in gait speed

29-10-2019 – Yusuke Osawa, Nancy Chiles Shaffer, Michelle D. Shardell, Stephanie A. Studenski, Luigi Ferrucci

Journal Article

Abstract
Background
Slow gait speed is a powerful predictor of disability in activities of daily living and mortality. Muscle strength and body composition change over time, but their changes differ by sex. How these parameters jointly affect gait speed decline is unknown. Understanding this association could help develop and evaluate the sex‐specific effects of lifestyle interventions to delay gait speed decline in older adults. We assessed whether changes in strength (Δstrength), appendicular lean mass (ΔALM), and fat mass (Δfat) jointly relate to change in gait speed and whether the association differs by sex.
Methods
The analytic sample comprised 575 women and 539 men aged 22–95 years enrolled in the Baltimore Longitudinal Study of Aging. Mean follow‐up was 4.0 years. Measures included isometric knee extension strength, dual‐energy X‐ray absorptiometry‐assessed ALM and fat mass, and gait speed from the 400 m fast pace walk. Sex‐specific linear mixed models were adjusted for follow‐up time and baseline age, race, height, ALM, fat mass, peak torque, and gait speed. We also included second‐order interaction terms of the key predictive variables (e.g. Δstrength × ΔALM). To interpret the interactions, we estimated average gait declines using the 25th or 75th percentile of the two significant predictive variables and then assessed which condition relates to larger decline in gait speed.
Results
In both sexes, independent of ΔALM and Δfat, larger decline in strength significantly related to larger decline in gait speed (P = 0.01 for both sexes). In men, interactions between Δstrength × ΔALM and Δfat by ΔALM were associated with change in gait speed; men with greater declines in both muscle strength and ALM or greater declines in both ALM and fat have steeper gait speed decline. In contrast, in women, the interaction between Δfat and ΔALM was associated with change in gait speed; women with an increase in fat mass combined with less decline in ALM have steeper gait speed decline.
Conclusions
While change in strength affects change in gait speed in both sexes, the effects of body composition change differ by sex. Dual‐energy X‐ray absorptiometry‐based estimates of lean mass may be confounded by intramuscular fat. Future studies should examine sex‐specific combined effects of change in strength and body composition on mobility using multiple techniques to measure body composition. Intervention studies should consider testing sex‐specific interventions on body composition.

Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)

29-10-2019 – Pradeep Harish, Alberto Malerba, Ngoc Lu‐Nguyen, Leysa Forrest, Ornella Cappellari, Fanny Roth, Capucine Trollet, Linda Popplewell, George Dickson

Journal Article

Abstract
Background
Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset muscle disease affecting one per 80 000 of the general population characterized by profound dysphagia and ptosis, and limb weakness at later stages. Affected muscles are characterized by increased fibrosis and atrophy. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to ameliorate symptoms in dystrophic muscles.
Methods
In this study, we performed a systemic delivery of a monoclonal antibody to immunologically block myostatin in the A17 mouse model of OPMD. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which histological analyses were performed on the samples.
Results
This treatment significantly (P < 0.01) improved body mass (11%) and muscle mass (for the tibialis anterior and extensor digitorum longus by 19% and 41%) in the A17 mice treated with RK35 when compared to saline controls. Similarly, a significantly (P < 0.01) increased muscle strength (18% increase in maximal tetanic force) and myofibre diameter (17% and 44% for the tibialis anterior and extensor digitorum longus), and reduced expression of markers of muscle fibrosis (40% reduction in area of expression), was also observed. No change in the density of intranuclear inclusions (a hallmark of disease progression of OPMD) was however observed.
Conclusions
Our study supports the clinical translation of such antibody‐mediated inhibition of myostatin as a treatment of OPMD. This strategy has implications to be used as adjuvant therapies with gene therapy based approaches, or to stabilize the muscle prior to myoblast transplantation.

Appetite and food intake results from phase I studies of anamorelin

29-10-2019 – Robert A. Blum, Stuart Mair, Elizabeth M. Duus

Journal Article

Abstract
Background
Loss of appetite and body weight are potentially devastating, highly prevalent cancer complications. The ghrelin receptor is a mediator of appetite and metabolism, and anamorelin is a novel, orally administered ghrelin receptor agonist. Effects on appetite and food intake may influence body‐weight gain but can be difficult to measure in multi‐site studies. Here, we summarize two single‐centre trials.
Methods
Both trials were phase I, randomized, double‐blind, placebo‐controlled, partly/wholly crossover studies of healthy young adults. Study 102 tested single anamorelin doses of 1–20 mg. Assessments included post‐dose self‐ratings on 100 mm visual analogue scales for hunger, anticipated eating pleasure, and anticipated quantity of food consumption. Study 101 tested single 10, 25, and 50 mg doses. Assessments included the same scales plus caloric intake beginning 4 h post‐dose.
Results
Study 102 treated 16 male subjects (mean age, 26.3 years). Mean hunger scores generally increased after all treatments, with significant differences from placebo (P < 0.05) in the 5 mg anamorelin group at 0.5 and 1 h post‐dose (+8.2 and +13.2 mm). Results for other scales were similar. Study 101 treated nine male subjects (mean age, 26.3 years). Pooled findings for anamorelin 25 and 50 mg vs. placebo showed significant mean increases in hunger scores at all but 1 pre‐prandial time point, including the first assessment, 0.5 h post‐dose (+10.9 vs. +0.7 mm, P = 0.0077), and the last assessment, 4 h post‐dose (+32.7 vs. +7.0 mm, P = 0.0170), with a significant mean 18.4% increase vs. placebo in caloric intake (P = 0.0148).
Conclusions
In single‐centre studies of healthy adults, single anamorelin doses of 1–20 mg elicited modest increases in hunger, and single doses of 25 and 50 mg achieved significant increases in hunger and caloric intake. The findings are consistent with dose‐related weight gain reported in a prior phase I study as well as multi‐centre findings in cachectic cancer patients and expand the evidence supporting anamorelin as a potential intervention.

Is muscle failure a better term than sarcopenia?

29-10-2019 – Charlotte Suetta, Andrea B. Maier

Letter

Prevalence, incidence, and clinical impact of cognitive–motoric risk syndrome in Europe, USA, and Japan: facts and numbers update 2019

29-10-2019 – Marcello Maggio, Fulvio Lauretani

Editorial

Abstract
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 In
CHIANTI 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.

Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2019

29-10-2019 – Stephan Haehling, John E. Morley, Andrew J. S. Coats, Stefan D. Anker

Editorial

Abstract
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Issue Information

29-10-2019 –

No abstract is available for this article.

Corrigendum

29-10-2019 –

Published Erratum

Skeletal muscle mTORC1 regulates neuromuscular junction stability

25-10-2019 – 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

Journal Article

Abstract
Background
Skeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (m
TORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of m
TORC1 signalling in adult skeletal muscle homeostasis is still not well defined.
Methods
Inducible, muscle‐specific Raptor and m
TOR 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 m
TOR 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 m
TOR 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 m
TOR 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 m
TORC1 in skeletal muscle during and after exercise.

Myopalladin promotes muscle growth through modulation of the serum response factor pathway

24-10-2019 – 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

Journal Article

Abstract
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.

Association of change in muscle mass assessed by D3‐creatine dilution with changes in grip strength and walking speed

17-10-2019 – 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

Journal Article

Abstract
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.

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

30-09-2019 – 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

Journal Article

Abstract
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); m
RNA 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. m
TOR, 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 m
RNA (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.

Disease‐induced and treatment‐induced alterations in body composition in locally advanced head and neck squamous cell carcinoma

19-09-2019 – 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

Journal Article

Abstract
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.

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

11-09-2019 – Lingxiao He, Praval Khanal, Christopher I. Morse, Alun Williams, Martine Thomis

Journal Article

Abstract
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 Methylation
EPIC Bead
Chip arrays. Differentially methylated cytosin–phosphate–guanine sites (dm
Cp
Gs) were identified at a P value threshold of 0.01 by comparing methylation levels between the sarcopenic and non‐sarcopenic groups at each Cp
G site. dm
Cp
G‐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 Cp
G sites (n = 788 074) showed no significant difference between the sarcopenic and non‐sarcopenic groups (0.812), while the average methylation level of dm
Cp
Gs (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 3UTR regions. In respect of Cp
G regions, Cp
G islands in promoters and some intragenic regions showed greater levels of methylation in the sarcopenic group. dm
Cp
G‐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.

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

11-09-2019 – Jiao Wu, Jiangling Dong, Daniela Verzola, Keith Hruska, Giacomo Garibotto, Zhaoyong Hu, William E. Mitch, Sandhya S. Thomas

Journal Article

Abstract
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 p
Akt 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.

Prognostic role of body composition parameters in gastric/gastroesophageal junction cancer patients from the EXPAND trial

28-08-2019 – Ulrich T. Hacker, Dirk Hasenclever, Nicolas Linder, Gertraud Stocker, Hyun‐Cheol Chung, Yoon‐Koo Kang, Markus Moehler, Harald Busse, Florian Lordick

Journal Article

Abstract
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.

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

23-08-2019 – 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

Journal Article

Abstract
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/Mu
RF1, Fbxo32/Atrogin1, and Fbxo30/Mu
SA1.
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.

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

22-08-2019 – Rebeka Tomasin, Ana Carolina Baptista Moreno Martin, Márcia Regina Cominetti

Journal Article, Review

Abstract
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.

Predictivity of bioimpedance phase angle for incident disability in older adults

22-08-2019 – Kazuki Uemura, Takehiko Doi, Kota Tsutsumimoto, Sho Nakakubo, Min‐Ji Kim, Satoshi Kurita, Hideaki Ishii, Hiroyuki Shimada

Journal Article

Abstract
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.

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

21-08-2019 – Kristine Pettersen, Sonja Andersen, Anna Veen, Unni Nonstad, Shinji Hatakeyama, Christian Lambert, Estelle Lach‐Trifilieff, Siver Moestue, Jana Kim, Bjørn Henning Grønberg, Alain Schilb, Carsten Jacobi, Geir Bjørkøy

Journal Article

Abstract
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 m
RNA 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/m
L, 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.

Defining barriers to implementation of nutritional advice in patients with cachexia

21-08-2019 – Rima Nasrah, Christina Van Der Borch, Mary Kanbalian, R. Thomas Jagoe

Journal Article

Abstract
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.

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

21-08-2019 – 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

Journal Article

Abstract
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 (Pr
Carb) 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), Pr
Carb, and 3‐nitrotyrosine were measured in 1450 individuals of the FRAILOMIC initiative. Participants were classified into robust, pre‐frail, and frail using Frieds 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 Pr
Carb 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 Pr
Carb (2.86; 1.82–4.49) than robust subjects in multivariate regression models.
Conclusions
Our study indicates that both low FMN and high Pr
Carb concentrations are associated with pre‐frailty and frailty.

Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure

20-08-2019 – 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

Journal Article

Abstract
Background
Previous studies in heart failure with reduced ejection fraction (HFr
EF) 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 HFr
EF.
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 HFr
EF 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 HFr
EF, respectively, which correlated to exercise capacity (r = 0.71; P > 0.0001). Female HFr
EF 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 HFr
EF patients.
Conclusions
These data provide novel evidence that HFr
EF 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 HFr
EF should consider targeting sex‐specific mitochondrial abnormalities in skeletal muscle.

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

20-08-2019 – Jennifer G. Le‐Rademacher, Elizabeth M. Storrick, Aminah Jatoi

Journal Article, Review

Abstract
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.

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

16-08-2019 – 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

Journal Article

Abstract
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), i
DXA, 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.

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

13-08-2019 – Mikel L. Sáez de Asteasu, Nicolás Martínez‐Velilla, Fabricio Zambom‐Ferraresi, Álvaro Casas‐Herrero, Eduardo L. Cadore, Robinson Ramirez‐Velez, Mikel Izquierdo

Journal Article

Abstract
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.

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

11-08-2019 – 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

Journal Article

Abstract
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 Fsts relevance to muscle wasting‐associated insulin‐resistant conditions in mice and humans.

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

09-08-2019 – Jacek T. Niedziela, Bartosz Hudzik, Krzysztof Strojek, Lech Poloński, Mariusz Gąsior, Piotr Rozentryt

Journal Article

Abstract
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 (HFr
EF) and DM.
Methods
The study comprised patients with HFr
EF 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 HFr
EF. 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 HFr
EF 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.

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

07-08-2019 – 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

Journal Article, Review

Abstract
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.

Associations between severe co‐morbidity and muscle measures in advanced non‐small cell lung cancer patients

06-08-2019 – Bjørn H. Grønberg, Christine Damgaard Valan, Tarje Halvorsen, Bjørg Sjøblom, Marit S. Jordhøy

Journal Article

Abstract
Background
Studies show that low skeletal muscle index (SMI) and low skeletal muscle density (SMD) are negative prognostic factors and associated with more toxicity from systemic therapy in cancer patients. However, muscle depletion can be caused by a range of diseases, and many cancer patients have significant co‐morbidity. The aim of this study was to investigate whether there were associations between co‐morbidity and muscle measures in patients with advanced non‐small cell lung cancer.
Methods
Patients in a Phase III trial comparing two chemotherapy regimens in advanced non‐small cell lung cancer were analysed (n = 436). Co‐morbidity was assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS‐G), which rates co‐morbidity from 0 to 4 on 14 different organ scales. Severe co‐morbidity was defined as having any grades 3 and 4 CIRS‐G score. Muscle measures were assessed from baseline computed tomography slides at the L3 level using the Slice
OMatic software.
Results
Complete data were available for 263 patients (60%). Median age was 66, 57.0% were men, 78.7% had performance status 0–1, 25.9% Stage IIIB, 11.4% appetite loss, 92.4% were current/former smokers, 22.8% were underweight, 43.7% had normal weight, 26.6% were overweight, and 6.8% obese. The median total CIRS‐G score was 7 (range: 0–16), and 48.2% had severe co‐morbidity. Mean SMI was 44.7 cm2/m2 (range: 27–71), and the mean SMD was 37.3 Hounsfield units (HU) (range: 16–60). When comparing patients with and without severe co‐morbidity, there were no significant differences in median SMI (44.5 vs. 44.1 cm2/m2; 0.70), but patients with severe co‐morbidity had a significantly lower median SMD (36 HU vs. 39 HU; 0.001), mainly due to a significant difference in SMD between those with severe heart disease and those without (32.5 vs. 37.9 HU; 0.002). Linear regression analyses confirmed the association between severe co‐morbidity and SMD both in the simple analysis (0.001) and the multiple analysis (0.037) adjusting for baseline characteristics. Stage of disease, gender, and body mass index (BMI) were significantly associated with SMI in both the simple and multiple analyses. Age and BMI were significantly associated with SMD in the simple analysis; and age, gender, and BMI were significantly associated in the multiple analysis.
Conclusions
There were no significant differences in SMI between patients with and patients without severe co‐morbidity, but patients with severe co‐morbidity had lower SMD than other patients, mainly due to severe heart disease. Co‐morbidity might be a confounder in studies of the clinical role of SMD in cancer patients.

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

16-07-2019 – Benjamin F. Miller, Leslie M. Baehr, Robert V. Musci, Justin J. Reid, Frederick F. Peelor, Karyn L. Hamilton, Sue C. Bodine

Journal Article

Abstract
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.

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

15-07-2019 – Yeshun Wu, Bin Zhu, Zijun Chen, Jiahao Duan, Ling Yang

Letter

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

15-07-2019 – 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

Journal Article

Abstract
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.

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

21-06-2019 – 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

Journal Article

Abstract
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 (m
VDR) 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, m
VDR mice showed a normal body size. The m
VDR 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, m
VDR 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 m
RNA was lower in m
VDR 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.

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

17-06-2019 – 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

Journal Article

Abstract
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.