Article first published online:  22 March 2020

Ben Kirk, Jesse Zanker, Gustavo Duque

Osteosarcopenia: epidemiology, diagnosis, and treatment—facts and numbers
Background
Osteosarcopenia, the presence of osteopenia/osteoporosis and sarcopenia, is an emerging geriatric giant, which poses a serious global health burden.
Methods and results
The prevalence of osteosarcopenia ranges in community‐dwelling older adults [5– 37% (≥65 years)] with the highest rates observed in those with fractures (low‐trauma fracture: ~46%; hip fracture: 17.1– 96.3%). Among 2353 community‐dwelling adults, risk factors associated with osteosarcopenia include older age [men: 14.3% (60– 64 years) to 59.4% (≥75 years); women: 20.3% (60– 64 years) to 48.3% (≥75 years), P  < 0.05], physical inactivity [inverse relationship: 0.64, 95% confidence interval (CI) 0.46–0.88 (sexes combined)], low body mass index (inverse relationship: men: 0.84, 95% CI 0.81–0.88; women: 0.77, 95% CI 0.74–0.80), and higher fat mass (men: 1.46, 95% CI 1.11–1.92; women: 2.25, 95% CI 1.71–2.95). Among 148 geriatric inpatients, osteosarcopenic individuals demonstrate poorer nutritional status (mini‐nutritional assessment scores: 8.50 ± 2.52 points, P  < 0.001) vs. osteoporosis or sarcopenia alone, while among 253 older Australians, osteosarcopenia is associated with impaired balance and functional capacity [odds ratios (ORs): 2.56– 7.19; P  < 0.05] vs. non‐osteosarcopenia. Osteosarcopenia also associates with falls (ORs: 2.83– 3.63; P  < 0.05), fractures (ORs: 3.86– 4.38; P  < 0.05), and earlier death [hazard ratio (1‐year follow‐up): 1.84, 95% CI; 0.69– 4.92, P  = 0.023] vs. non‐osteosarcopenia.
Conclusions
This syndrome is expected to grow in age‐related and disease‐related states, a likely consequence of immunosenescence coinciding with increased sedentarism, obesity, and fat infiltration of muscle and bone. Evidence suggests the pathophysiology of osteosarcopenia includes genetic polymorphisms, reduced mechanical loading, and impaired endocrine functioning, as well as altered crosstalk between muscle, bone, and fat cells. Clinicians should screen for osteosarcopenia via imaging methods (i.e. dual‐energy X‐ray absorptiometry) to quantify muscle and bone mass, in addition to assessing muscle strength (i.e. grip strength) and functional capacity (i.e. gait speed). A comprehensive geriatric assessment, including medical history and risk factors, must also be undertaken. Treatment of this syndrome should include osteoporotic drugs [bone anabolics/antiresorptives (i.e. teriparatide, denosumab, bisphosphates)] where indicated, and progressive resistance and balance exercises (at least 2‐3 times/week). To maximize musculoskeletal health, nutritional recommendations [protein (1.2– 1.5 g/kg/day), vitamin D (800–1000 IU/day), calcium (1300 mg/day), and creatine (3– 5 g/day)] must also be met. It is anticipated that diagnosis and treatment for osteosarcopenia will become part of routine healthcare in the future. However, further work is required to identify biomarkers, which, in turn, may increase diagnosis, risk stratification, and targeted treatments to improve health outcomes.

Kirk, B., Zanker, J., and Duque, G. (2020) Osteosarcopenia: epidemiology, diagnosis, and treatment—facts and numbers, Journal of Cachexia, Sarcopenia and Muscle, 11, 609– 618. https://doi.org/10.1002/jcsm.12567.

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     Article first published online:  06 March 2020

Sara Peixoto da Silva, Joana M.O. Santos, Maria Paula Costa e Silva, Rui M. Gil da Costa, Rui Medeiros

Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia
Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass, along with adipose tissue wasting, systemic inflammation and other metabolic abnormalities leading to functional impairment. Cancer cachexia has long been recognized as a direct cause of complications in cancer patients, reducing quality of life and worsening disease outcomes. Some related conditions, like sarcopenia (age‐related muscle wasting), anorexia (appetite loss) and asthenia (reduced muscular strength and fatigue), share some key features with cancer cachexia, such as weakness and systemic inflammation. Understanding the interplay and the differences between these conditions is critical to advance basic and translational research in this field, improving the accuracy of diagnosis and contributing to finally achieve effective therapies for affected patients.
carriers for research strategies of many diseases, we propose that exosomes could be a potential research direction or strategies of sarcopenia in the future.

da Silva, S. P., Santos, J. M. O., Costa e Silva, M. P., Gil da Costa, R. M., and Medeiros, R. (2020) Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia, Journal of Cachexia, Sarcopenia and Muscle, 11, 619– 635. https://doi.org/10.1002/jcsm.12528.

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     Article first published online:  06 March 2020

Linda B.M. Weerink, Anouk van der Hoorn, Barbara L. van Leeuwen, Geertruida H. de Bock

Low skeletal muscle mass and postoperative morbidity in surgical oncology: a systematic review and meta‐analysis
Background
Sarcopenia might function as an indicator for frailty, and as such as a risk factor for the development of postoperative complications. The aim of this study was to meta‐analyse the relation between preoperative sarcopenia and the development of severe postoperative complications in patients undergoing oncological surgery.
Methods
PubMed and Embase databases were systematically searched from inception until May 2018. Included were studies reporting on the incidence of severe postoperative complications and radiologically determined preoperative sarcopenia. Studies reporting the skeletal muscle as a continuous variable only were excluded. Data were extracted independently by two reviewers. Random effect meta‐analyses were applied to estimate the pooled odds ratio (OR) with 95% confidence intervals (95% CI) for severe postoperative complications, defined as Clavien‐Dindo grade ≥3, including 30‐day mortality. Heterogeneity was evaluated with I 2 testing. Analyses were performed overall and stratified by measurement method, tumour location and publication date.
Results
A total of 1924 citations were identified, and 53 studies (14 295 patients) were included in the meta‐analysis. When measuring the total skeletal muscle area, 43% of the patients were sarcopenic, versus 33% when measuring the psoas area. Severe postoperative complications were present in 20%, and 30‐day mortality was 3%. Preoperative sarcopenia was associated with an increased risk of severe postoperative complications (ORpooled: 1.44, 95% CI: 1.24–16.8, P <0.001, I 2=55%) and 30‐day mortality (ORpooled: 2.15, 95% CI: 1.46–3.17, P <0.001, I 2=14%). A low psoas mass was a stronger predictor for severe postoperative complications compared with a low total skeletal muscle mass (ORpooled: 2.06, 95% CI: 1.37–3.09, ORpooled: 1.32, 95% CI: 1.14–1.53, respectively) and 30‐day mortality [ORpooled: 6.17 (95% CI: 2.71–14.08, ORpooled: 1.80 (95% CI: 1.24–2.62), respectively]. The effect was independent of tumour location and publication date.
Conclusions
The presence of low psoas mass prior to surgery, as an indicator for sarcopenia, is a common phenomenon and is a strong predictor for the development of postoperative complications. The presence of low total skeletal muscle mass, which is even more frequent, is a less informative predictor for postoperative complications and 30‐day mortality. The low heterogeneity indicates that the finding is consistent over studies. Nevertheless, the value of sarcopenia relative to other assessments such as frailty screening is not clear. Research is needed in order to determine the place of sarcopenia in future preoperative risk stratification.

Weerink, L. B. M., van der Hoorn, A., van Leeuwen, B. L., and de Bock, G. H. (2020) Low skeletal muscle mass and postoperative morbidity in surgical oncology: a systematic review and meta‐analysis, Journal of Cachexia, Sarcopenia and Muscle, 11, 636– 649. https://doi.org/10.1002/jcsm.12529.

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     Article first published online:  05 March 2020

Liang‐Kung Chen, An‐Chun Hwang, Wei‐Ju Lee, Li‐Ning Peng, Ming‐Hsien Lin, David L. Neil, Shu‐Fang Shih, Ching‐Hui Loh, Shu‐Ti Chiou on behalf of the Taiwan Health Promotion Intervention Study for Elders research group

Efficacy of multidomain interventions to improve physical frailty, depression and cognition: data from cluster‐randomized controlled trials
Background
Frailty is the pre‐eminent exigency of aging. Although frailty‐related impairments are preventable, and multidomain interventions appear more effective than unimodal ones, the optimal components remain uncertain.
Methods
We devised multidomain interventions against physical and cognitive decline among prefrail/frail community‐dwelling ≥65‐year‐olds and evaluated these in complementary cluster‐randomized trials of efficacy and participant empowerment. The Efficacy Study compared ~3‐monthly telephone consultations vs. 16, 2 h sessions/year comprising communally partaken physical and cognitive training plus nutrition and disease education; the Empowerment Study compared the standard Efficacy Study multidomain intervention (Sessions 1–10) vs. an enhanced version redesigned to empower and motivate individual participants. Changes from baseline in physical, functional, and cognitive performance were measured after 6 and 12 months in the Efficacy Study and after 6 months in the Empowerment Study , with post‐intervention follow‐up at 9 months. Primary outcomes are as follows: Cardiovascular Health Study frailty score; gait speed; handgrip strength; and Montreal Cognitive Assessment (MoCA). Secondary outcomes are as follows: instrumental activities of daily living; metabolic equivalent of task (MET); depressed mood (Geriatric Depression Scale‐5 ≥2); and malnutrition (Mini‐Nutritional Assessment short‐form ≤11). Intervention effects were analyzed using a generalized linear mixed model.
Results
Efficacy Study participants (n = 1082, 40 clusters) were 75.1 ± 6.3 years old, 68.7% women, and 64.7% prefrail/frail; analytic clusters: 19 intervention (410/549 completed) vs. 21 control (375/533 completed). Empowerment Study participants (n = 440, 14 clusters) were 75.9 ± 7.1 years old, 83.6% women, and 56.7% prefrail/frail; analytic clusters: seven intervention (209/230 completed) vs. seven control (189/210 completed). The standard and enhanced multidomain interventions both reduced frailty and significantly improved aspects of physical, functional, and cognitive performance, especially among ≥75‐year‐olds. Standard multidomain intervention decreased depression [odds ratio 0.56, 95% confidence interval (CI) 0.32, 0.99] and malnutrition (odds ratio 0.45, 95% CI 0.26, 0.78) by 12 months and improved concentration at Months 6 (0.23, 95% CI 0.04, 0.42) and 12 (0.46, 95% CI 0.22, 0.70). Participant empowerment augmented activity (4.67 MET/h, 95% CI 1.64, 7.69) and gait speed (0.06 m/s, 95% CI 0.00, 0.11) at 6 months, with sustained improvements in delayed recall (0.63, 95% CI 0.20, 1.06) and MoCA performance (1.29, 95% CI 0.54, 2.03), and less prevalent malnutrition (odds ratio 0.39, 95% CI 0.18, 0.84), 3 months after the intervention ceased.
Conclusions
Pragmatic multidomain intervention can diminish physical frailty, malnutrition, and depression and enhance cognitive performance among community‐dwelling elders, especially ≥75‐year‐olds; this might supplement healthy aging policies, probably more effectively if participants are empowered.

Chen, L.‐K., Hwang, A.‐C., Lee, W.‐J., Peng, L.‐N., Lin, M.‐H., Neil, D. L., Shih, S.‐F., Loh, C.‐H., Chiou, S.‐T., and on behalf of the Taiwan Health Promotion Intervention Study for Elders research group (2020) Efficacy of multi domain interventions to improve physical frailty, depression and cognition: data from cluster‐randomized controlled trials, Journal of Cachexia, Sarcopenia and Muscle, 11, 650– 662. https://doi.org/10.1002/jcsm.12534.

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     Article first published online:  24 February 2020

Sigve N. Aas, Markus Breit, mStian Karsrud, Ole J. Aase, Simen H. Rognlien, Kristoffer T. Cumming, Carlo Reggiani, Olivier Seynnes, Andrea P. Rossi, Luana Toniolo, Truls Raastad

Musculoskeletal adaptations to strength training in frail elderly: a matter of quantity or quality?
Background
The improvement in muscle strength generally exceeds the increase in muscle size following strength training in frail elderly, highlighting the complex aetiology of strength deficit in aging. The aim of this study was to investigate the effect of heavy‐load strength training on a broad number of factors related to specific strength in frail elderly.
Methods
Thirty‐four frail elderly men (n = 18) and women (n = 16) aged 67 to 98 (86 ± 7 years) were randomized to either a group performing strength training twice a week for 10 weeks (ST) or a non‐exercising control group (CON). Knee extensor muscle strength was tested as one‐repetition maximum (1RM) and isometric maximal voluntary contraction (MVC) torque. Muscle activation was assessed by the interpolated twitch technique, and muscle density [mean Hounsfield units (HU)] and intermuscular adipose tissue (IMAT) by computed tomography scans of the quadriceps femoris. Muscle biopsies from the vastus lateralis were obtained to investigate changes in intramyocellular lipids and single‐fibre specific tension.
Results
In ST, knee extension 1RM and MVC improved by 17 and 7%, respectively. Muscle cross‐sectional area of the quadriceps femoris increased by 7%, accompanied by a 4% increase of muscle density. No changes in IMAT, voluntary activation level, single‐fibre specific tension, or lipid content were observed.
Conclusions
In contrast to several previous reports, the improvements in isometric muscle strength and muscle area were in good agreement in the present study. The training‐induced increase in muscle density was not due to changes in skeletal muscle lipid content. Instead, the increase in muscle density may reflect increased packing of contractile material or simply an increased ratio of muscle tissue relative to IMAT.

Aas, S. N., Breit, M., Karsrud, S., Aase, O. J., Rognlien, S. H., Cumming, K. T., Reggiani, C., Seynnes, O., Rossi, A. P., Toniolo, L., and Raastad, T. (2020) Musculoskeletal adaptations to strength training in frail elderly: a matter of quantity or quality?, Journal of Cachexia, Sarcopenia and Muscle, 11, 663– 677. https://doi.org/10.1002/jcsm.12543.

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     Article first published online:  05 February 2020

Aolin Yang, Qingqing Lv, Feng Chen, Yingfang Wang, Yixuan Liu, Wanying Shi, Ying Liu, Difei Wang

The effect of vitamin D on sarcopenia depends on the level of physical activity in older adults
Objective
Sarcopenia in older adults is closely related to vitamin D deficiency and reduced levels of physical activity, but little has been reported on the interaction between physical activity and the positive effects of vitamin D. The purpose of this study was to explore the interactive effect of vitamin D and physical activity on muscle mass and function through animal experiments and population surveys.
Methods
Male 4‐week‐old C57BL/6J mice were fed different purified diets: a vitamin D‐deficient diet (with increased calcium and phosphorus to prevent the effects of abnormal mineral levels on muscle) or a 1,25‐dihydroxyvitamin D3 (1,25D)‐supplemented diet. After 24 weeks on the assigned diets, the mice were immobilized. The level of skeletal muscle atrophy in the mice was determined by grip strength, gastrocnemius (GA) muscle mass and muscle fiber cross‐sectional area (CSA); additionally, the protein expression levels of FOXO3a and the E3 ubiquitin ligases MuRF1 and MAFbx were detected. A cross‐sectional study included data from 4139 older adults (64.9% women, 67.9 ± 6.7 years) as part of a survey in Shenyang, Northeast China. The associations of serum 25(OH)D3 and physical activity with timed up and go test (TUG) performance, handgrip strength, calf circumference, and body muscle mass were assessed by a linear regression analysis that was adjusted for covariates.
Results
In activity‐limited mice, vitamin D deficiency accelerated the decrease in GA muscle weight, muscle fiber CSA, and grip strength and increased the protein expression of MuRF1, MAFbx, and FOXO3a (all P < 0.05). In addition, 1,25D supplementation may inhibit the grip‐strength reduction induced by limited activity (P = 0.069). Serum 25(OH)D3 and physical activity were linearly related to TUG time (P < 0.001) and handgrip strength (P < 0.05) after adjustment for sex, age, body mass index (BMI), education level, smoking status, and serum calcium level. Serum 25(OH)D3 and physical activity had interactive effects on TUG (P < 0.001) and handgrip strength (P < 0.05) but not calf circumference or body muscle mass in older adults.
Conclusions
The effect of vitamin D on muscle strength and physical performance depends on physical activity level in the elderly. It is recommended that older adults strive to avoid both physical inactivity and vitamin D deficiency. Because physical inactivity and vitamin D deficiency may exacerbate muscle atrophy, the biological mechanism may involve synergistic effects of vitamin D and physical activity on the promotion of muscle protein ubiquitination and degradation.

Yang, A., Lv, Q., Chen, F., Wang, Y., Liu, Y., Shi, W., Liu, Y., and Wang, D. (2020) The effect of vitamin D on sarcopenia depends on the level of physical activity in older adults, Journal of Cachexia, Sarcopenia and Muscle, 11, 678– 689. https://doi.org/10.1002/jcsm.12545.

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     Article first published online:  15 February 2020

Sophia X. Sui, Kara L. Holloway‐Kew, Natalie K. Hyde, Lana J. Williams, Monica C. Tembo, Mohammadreza Mohebbi, Marlene Gojanovic, Sarah Leach, Julie A. Pasco

Handgrip strength and muscle quality in Australian women: cross‐sectional data from the Geelong Osteoporosis Study
Background
Low handgrip strength (HGS) is a measure of poor skeletal muscle performance and a marker of ill health and frailty. Muscle quality (MQ) is a measure of muscle strength relative to muscle mass. We aimed to develop normative data for HGS and MQ, report age‐related prevalence of low HGS and MQ, and determine the relationship with age, anthropometry, and body composition for women in Australia.
Methods
This cross‐sectional analysis included data from 792 women (ages 28–95 years) assessed by the Geelong Osteoporosis Study. Duplicate measures of HGS were performed for each hand with a dynamometer (Jamar) and the mean of maximum values used for analyses. Dual energy X‐ray absorptiometry‐derived lean mass for the arms was used to calculate MQ as HGS/lean mass (kg/kg). Body mass index (BMI) was categorized as normal (BMI < 25.0 kg/m2), overweight (25.0–29.9 kg/m2), and obese (>30.0 kg/m2). Fat mass index (FMI) was calculated as whole body fat/height2 (kg/m2) and appendicular lean mass index (ALMI) as lean mass of arms and legs/height2 (kg/m2).
Results
Mean (±SD) of HGS values for normal BMI, overweight, and obese groups were 25 (±7), 24 (±7), and 24 (±7) kg, P = 0.09, and for MQ, 12 (±3), 11 (±3), and 10 (±3) kg/kg, P < 0.001. Our data indicated a quadratic relationship between age and HGS or MQ. Mean HGS and MQ remained stable until the fifth age decade then declined steadily with increasing age; therefore, we used data for women (n = 283) aged 28–49 years as the young adult reference group, with mean (SD) values for HGS 28 (±6) kg and MQ 12 (±3) kg/kg. The prevalence of low (T‐score < −2) HGS and MQ for women 80 years and older was 52.2% and 39.6%, respectively. In multivariable models, age‐adjusted HGS was associated with FMI (B = −0.13, P = 0.004) and ALMI (1.03, <0.001) while age‐adjusted MQ was associated with BMI (−0.15, <0.001) but not with FMI. In a sensitivity analysis, the same pattern remained after the removal of 129 women who reported hand and/or arm pain.
Conclusions
Mean HGS and MQ declined with advancing age in older women. Our data suggest that while mean HGS increased with appendicular lean mass and decreased with body fat mass, there was no association with BMI. By contrast, MQ decreased with increasing BMI, but not with increasing adiposity.

Sui, S. X., Holloway‐Kew, K. L., Hyde, N. K., Williams, L. J., Tembo, M. C., Mohebbi, M., Gojanovic, M., Leach, S., and Pasco, J. A. (2020) Handgrip strength and muscle quality in Australian women: cross‐sectional data from the Geelong Osteoporosis Study, Journal of Cachexia, Sarcopenia and Muscle, 11, 690– 697. https://doi.org/10.1002/jcsm.12544.

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     Article first published online:  03 February 2020

Sarianna Sipilä, Timo Törmäkangas, Elina Sillanpää, Pauliina Aukee, Urho M. Kujala, Vuokko Kovanen, Eija K. Laakkonen

Muscle and bone mass in middle‐aged women: role of menopausal status and physical activity
Background
Women experience drastic hormonal changes during midlife due to the menopausal transition. Menopausal hormonal changes are known to lead to bone loss and potentially also to loss of lean mass. The loss of muscle and bone tissue coincide due to the functional relationship and interaction between these tissues. If and how physical activity counteracts deterioration in muscle and bone during the menopausal transition remains partly unresolved. This study investigated differences between premenopausal, early perimenopausal, late perimenopausal, and postmenopausal women in appendicular lean mass (ALM), appendicular lean mass index (ALMI), femoral neck bone mineral density (BMD) and T score. Furthermore, we investigated the simultaneous associations of ALM and BMD with physical activity in the above‐mentioned menopausal groups.
Methods
Data from the Estrogen Regulation of Muscle Apoptosis study were utilized. In total, 1393 women aged 47–55 years were assigned to premenopausal, early perimenopausal, late perimenopausal, and postmenopausal groups based on follicle‐stimulating hormone concentration and bleeding diaries. Of them, 897 were scanned for ALM and femoral neck BMD by dual‐energy X‐ray absorptiometry and ALMI (ALM/height2) and neck T scores calculated. Current level of leisure‐time physical activity was estimated by a validated self‐report questionnaire and categorized as sedentary, low, medium, and high.
Results
Appendicular lean mass, appendicular lean mass index, femoral neck bone mineral density, and and T score showed a significant linear declining trend across all four menopausal groups. Compared with the postmenopausal women, the premenopausal women showed greater ALM (18.2, SD 2.2 vs. 17.8, SD 2.1, P < 0.001), ALMI (6.73, SD 0.64 vs. 6.52, SD 0.62, P < 0.001), neck BMD (0.969, SD 0.117 vs. 0.925, SD 0.108, P < 0.001), and T score (−0.093, SD 0.977 vs −0.459, SD 0.902, P < 0.001). After adjusting for potential confounding pathways, a higher level of physical activity was associated with greater ALM among the premenopausal [β = 0.171; confidence interval (CI) 95% 0.063–0.280], late perimenopausal (β = 0.289; CI 95% 0.174–0.403), and postmenopausal (β =0.278; CI 95% 0.179–0.376) women. The positive association between femoral neck BMD and level of physical activity was significant only among the late perimenopausal women (β = 0.227; CI 95% 0.097–0.356).
Conclusions
Skeletal muscle and bone losses were associated with the menopausal transition. A higher level of physical activity during the different menopausal phases was beneficial, especially for skeletal muscle. Menopause‐related hormonal changes predispose women to sarcopenia and osteoporosis and further to mobility disability and fall‐related fractures in later life. New strategies are needed to promote physical activity among middle‐aged women. Longitudinal studies are needed to confirm these results.

Sipilä, S., Törmäkangas, T., Sillanpää, E., Aukee, P., Kujala, U., Kovanen, V., and Laakkonen, E. K. (2020) Muscle and bone mass in middle‐aged women: role of menopausal status and physical activity, Journal of Cachexia, Sarcopenia and Muscle, 11, 698– 709. https://doi.org/10.1002/jcsm.12547.

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     Article first published online:  07 February 2020

Young‐Gyun Seo, Hong Ji Song, Young Rim Song

Fat‐to‐muscle ratio as a predictor of insulin resistance and metabolic syndrome in Korean adults
Background
The present study evaluated the associations of the fat‐to‐muscle ratio (FMR) with metabolic syndrome (MetS) and insulin resistance (IR) in Korean adults using nationally representative survey data.
Methods
A two‐stage stratified sampling method was reflected in a cross‐sectional study involving a total of 13 032 participants aged ≥ 19 years who participated in the fourth and fifth Korea National Health and Nutrition Examination Surveys. The homeostasis model assessment for IR (HOMA‐IR) was used to evaluate IR and was calculated as follows: [fasting plasma glucose level (mg/dL) × fasting plasma insulin level (uIU/mL)]/405. MetS was defined using the 2006 International Diabetes Federation criteria, and FMR was measured using whole‐body dual‐energy X‐ray absorptiometry and calculated as follows: total fat mass (kg) divided by total lean mass (kg). In addition, the optimal FMR cut‐off values for detecting MetS and the odds ratios (ORs) for MetS risk were determined according to the FMR quartile and sex.
Results
Among all participants, the proportion of women was 58.4%, and the mean age was 44.22 ± 0.26 years. The FMR significantly differed between men and women (0.30 ± 0.002 vs. 0.53 ± 0.003, respectively, P  < 0.001), and the prevalence of MetS and IR gradually increased as FMR increased (P for trend: <0.001). The optimal FMR cut‐off value for detecting MetS was higher in women than in men (0.555 vs. 0.336, respectively). The negative predictive value was the highest in normal‐weight participants (0.9992 in women and 0.9986 in men), while the positive predictive value was the highest in obese participants (0.5994 in women and 0.5428 in men). Based on the derived cut‐off FMR, a high FMR was associated with poor outcomes in terms of cardiometabolic risk markers (P  < 0.001). The multivariable‐adjusted ORs for MetS, abdominal obesity, and IR (HOMA‐IR ≥ 3) were 5.35 [95% confidence interval (CI): 4.39–6.52], 7.67 (95% CI: 6.33–9.30), and 3.25 (95% CI: 2.70–3.92), respectively, in men and 5.59 (95% CI: 4.66–6.72), 7.48 (95% CI: 6.35–8.82), and 2.55 (95% CI: 2.17–3.00), respectively, in women.
Conclusions
In the present study, a high FMR was significantly associated with the prevalence of MetS and IR. The present findings also showed that FMR can be a novel indicator for detecting the absence or presence of MetS, particularly in metabolically healthy normal‐weight individuals and metabolically obese obese‐weight individuals.

Seo, Y.‐G., Song, H. J., and Song, Y. R. (2020) Fat‐to‐muscle ratio as a predictor of insulin resistance and metabolic syndrome in Korean adults, Journal of Cachexia, Sarcopenia and Muscle, 11, 710– 725. https://doi.org/10.1002/jcsm.12548.

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     Article first published online:  05 February 2020

Jong Hyun Jhee, Young Su Joo, Seong Hyeok Han, Tae‐Hyun Yoo, Shin‐Wook Kang, Jung Tak Park

High muscle‐to‐fat ratio is associated with lower risk of chronic kidney disease development
Background
Obesity, a known risk factor for chronic kidney disease (CKD), is generally assessed using body mass index (BMI). However, BMI may not effectively reflect body composition, and the impact of muscle‐to‐fat (MF) mass balance on kidney function has not been elucidated. This study evaluated the association between body muscle and fat mass balance, represented as the MF ratio, and incident CKD development.
Methods
Data were retrieved from a prospective community‐based cohort study (Korean Genome and Epidemiology Study). Muscle and fat mass were measured using multifrequency bioelectrical impedance analysis. The study endpoint was incident CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 in at least two or more consecutive measurements during the follow‐up period).
Results
Totally, 7682 participants were evaluated. Their mean age was 51.7 ± 8.7 years, and 48% of the subjects were men. During a median follow‐up of 140.0 (70.0–143.0) months, 633 (8.2%) subjects developed incident CKD. When the association between body composition and incident CKD was investigated, multivariable Cox proportional hazard analysis revealed that increase in MF ratio was related with a decreased risk of CKD development [per 1 increase in MF ratio: hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.77–0.96; P = 0.008]. This association was also maintained when MF ratio was dichotomized according to sex‐specific median values (high vs. low: HR, 0.83; 95% CI, 0.70–0.98; P = 0.031). Analyses preformed in a propensity score matched group also revealed a similar decreased risk of incident CKD in high MF ratio participants (high vs. low: HR, 0.84; 95% CI, 0.71–0.98; P = 0.037). This relationship between MF ratio and incident CKD risk was consistently significant across subgroups stratified by age, sex, hypertension, estimated glomerular filtration rate categories, and proteinuria. Among different BMI groups (normal, overweight, and obese), the relationship between high MF ratio and lower incident CKD risk was significant only in overweight and obese subjects.
Conclusions
Lower fat mass relative to muscle mass may lower the risk of CKD development in individuals with normal renal function. This relationship seems more prominent in overweight and obese subjects than in normal weight subjects.

Jhee, J. H., Joo, Y. S., Han, S. H., Yoo, T.‐H., Kang, S.‐W., and Park, J. T. (2020) High muscle‐to‐fat ratio is associated with lower risk of chronic kidney disease development, Journal of Cachexia, Sarcopenia and Muscle, 11, 726– 734. https://doi.org/10.1002/jcsm.12549.

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     Article first published online:  27 January 2020

Amritpal S. Bhullar, Ana Anoveros‐Barrera, Abha Dunichand‐Hoedl, Karen Martins, David Bigam, mRachel G. Khadaroo, Todd McMullen, Oliver F. Bathe, Charles T. Putman, Michael T. Clandinin, Vickie E. Baracos, Vera C. Mazurak

Lipid is heterogeneously distributed in muscle and associates with low radiodensity in cancer patients
Background
Low muscle radiodensity is associated with mortality in a variety of cancer types. Biochemical and morphological correlates are unknown. We aimed to evaluate triglyceride (TG) content and location as a function of computed tomography (CT)‐derived measures of skeletal muscle radiodensity in cancer patients.
Methods
Rectus abdominis (RA) biopsies were collected during cancer surgery from 75 patients diagnosed with cancer. Thin‐layer chromatography and gas chromatography were used for quantification of TG content of the muscle. Axial CT images of lumbar vertebra were used to measure muscle radiodensity. Oil Red O staining was used to determine the location of neutral lipids in frozen muscle sections.
Results
There was wide variation in RA radiodensity in repeated measures (CV% ranged from 3 to 55% based on 10 serial images) as well as within one slice (CV% ranged from 6 to 61% based on 10 subregions). RA radiodensity and total lumbar muscle radiodensity were inversely associated with TG content of RA (r = −0.396, P < 0.001, and r = −0.355, P = 0.002, respectively). Of the total percentage area of muscle staining positive for neutral lipid, 54 ± 17% was present as extramyocellular lipids (range 23.5–77.8%) and 46 ± 17% (range 22.2–76.5%) present as intramyocellular lipid droplets.
Conclusions
Repeated measures revealed wide variation in radiodensity of RA muscle, both vertically and horizontally. Low muscle radiodensity reflects high level of TG in patients with cancer. Non‐uniform distribution of intramyocellular and extramyocellular lipids was evident using light microscopy. These results warrant investigation of mechanisms resulting in lipid deposition in muscles of cancer patients.

Bhullar, A. S., Anoveros‐Barrera, A., Dunichand‐Hoedl, A., Martins, K., Bigam, D., Khadaroo, R. G., McMullen, T., Bathe, O. F., Putman, C. T., Clandinin, M. T., Baracos, V. E., and Mazurak, V. C. (2020) Lipid is heterogeneously distributed in muscle and associates with low radiodensity in cancer patients, Journal of Cachexia, Sarcopenia and Muscle, 11, 735– 747. https://doi.org/10.1002/jcsm.12533.

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     Article first published online:  13 February 2020

Michael P. Chu, Yuetong Li, Sunita Ghosh, Shelley Sass, Michael Smylie, John Walker, Michael B. Sawyer

Body composition is prognostic and predictive of ipilimumab activity in metastatic melanoma
Background
Body composition is minimally investigated in an immunotherapy era. Specific body composition signals such as myosteatosis may reflect aspects of patients' immunology and thereby their ability to respond to immunotherapies. Ipilimumab is a key checkpoint inhibitor in metastatic melanoma. As an antibody, it may also be more accurately dosed using body composition parameters rather than weight alone. This retrospective study aimed to investigate body composition‐based dosing and outcomes.
Methods
Pretreatment computed tomography images from metastatic melanoma, ipilimumab‐treated patients from 2009 to 2014 were used to measure myosteatosis [skeletal muscle radiographic density or SMD, in Hounsfield units (HU)] and surface area (cm2) as previously described. Cut point analysis determined whether a level of ipilimumab dose and myosteatosis demonstrated differences in progression‐free (PFS) and overall survival (OS). Secondary endpoints included objective response rates and toxicities.
Results
Of 121 identified, 97 patients were evaluable. Baseline demographics included 56 years median age, 60% male participants, and 23.7% with BRAF mutations. SMD analysis identified cut‐offs of SMD < 42 in those with BMI < 25 kg/m2 and <20 HU in those with BMI ≥ 25 kg/m2, respectively. Low SMD patients had poorer median PFS [2.4 vs. 2.7 months, hazard ratio (HR) 1.76, P = 0.008] and OS (5.4 vs. 17.5 months, HR 2.47, P = 0.001), which remained significant in multivariate modelling. High SMD patients had more immune‐related adverse events, better objective response rates (17.9 vs. 3.3%, P = 0.051), and lower baseline neutrophil‐to‐lymphocyte ratio (21 vs. 39%, P = 0.049). Separately, patients receiving <2.03 mg/cm2 had improved median PFS (3.0 vs. 2.6 months, HR 1.88, P = 0.02) and OS (14.9 vs. 5.7 months, HR 1.98, P = 0.01).
Conclusions
Low SMD and receiving >2.03 mg/cm2 are prognostic of poorer melanoma outcomes post ipilimumab. SMD may identify patients with flawed immunology and predict who may better respond to such therapy. Ipilimumab dosing by skeletal muscle index stands in contrast to weight‐based dosing and may demonstrate a more accurate method of antibody dosing.

Chu, M. P., Li, Y., Ghosh, S., Sass, S., Smylie, M., Walker, J., and Sawyer, M. B. (2020) Body composition is prognostic and predictive of ipilimumab activity in metastatic melanoma, Journal of Cachexia, Sarcopenia and Muscle, 11, 748– 755. https://doi.org/10.1002/jcsm.12538.

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     Article first published online:  25 February 2020

Eliza R.C. Hagens, Minke L. Feenstra, Maarten A. van Egmond, Hanneke W.M. van Laarhoven, Maarten C.C.M. Hulshof, Piers R. Boshier, Donald E. Low, Mark I. van Berge Henegouwen, Suzanne S. Gisbertz

Influence of body composition and muscle strength on outcomes after multimodal oesophageal cancer treatment
Background
Influence of sarcopenia in combination with other body composition parameters and muscle strength on outcomes after oesophageal surgery for oesophageal cancer remains unclear. The objectives were (i) to describe the incidence of sarcopenia in relation to adipose tissue quantity and distribution and muscle strength; (ii) to evaluate if neoadjuvant chemoradiation (nCRTx) influences body composition and muscle strength; and (iii) to evaluate the influence of body composition and muscle strength on post‐operative morbidity and long‐term survival.
Methods
This retrospective study included patients with oesophageal cancer who received nCRTx followed by surgery between January 2011 and 2016. Skeletal muscle, visceral, and subcutaneous adipose tissue cross‐sectional areas were calculated based on computed tomography scans, and muscle strength was measured using hand grip tests, 30 seconds chair stand tests, and maximal inspiratory and expiratory pressure tests prior to nCRTx and after nCRTx.
Results
A total of 322 patients were included in this study. Sarcopenia was present in 55.6% of the patients prior to nCRTx and in 58.2% after nCRTx (P  = 0.082). Patients with sarcopenia had a significantly lower muscle strength and higher fat percentage. The muscle strength and incidence of sarcopenia increased while the mean body mass index and fat percentage decreased during nCRTx. A body mass index above 25 kg/m2 was associated with anastomotic leakage (P  = 0.032). Other body composition parameters were not associated with post‐operative morbidity. A lower handgrip strength prior to nCRTx was associated with pulmonary and cardiac complications (P  = 0.023 and P  = 0.009, respectively). In multivariable analysis, a lower number of stands during the 30 seconds chair stand test prior to nCRTx (hazard ratio 0.93, 95% confidence interval 0.87–0.99, P  = 0.017) and visceral adipose tissue of >128 cm2 after nCRTx (hazard ratio 1.81, 95% confidence interval 1.30–2.53, P  = 0.001) were associated with worse overall survival.
Conclusions
Sarcopenia occurs frequently in patients with oesophageal cancer and is associated with less muscle strength and a higher fat percentage. Body composition changes during nCRTx did not influence survival. Impaired muscle strength and a high amount of visceral adipose tissue are associated with worse survival. Therefore, patients with poor fitness might benefit from preoperative nutritional and muscle strengthening guidance, aiming to increase muscle strength and decrease visceral adipose tissue. However, this should be confirmed in a large prospective study.

Hagens, E. R. C., Feenstra, M. L., van Egmond, M. A., van Laarhoven, H. W. M., Hulshof, M. C. C. M., Boshier, P. R., Low, D. E., van Berge Henegouwen, M. I., and Gisbertz, S. S. (2020) Influence of body composition and muscle strength on outcomes after multimodal oesophageal cancer treatment, Journal of Cachexia, Sarcopenia and Muscle, 11, 756– 767. https://doi.org/10.1002/jcsm.12540.

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     Article first published online:  07 February 2020

Haiyan Zhou,Jinhong Meng, Alberto Malerba, Francesco Catapano, Palittiya Sintusek, Susan Jarmin, Lucy Feng, Ngoc Lu‐Nguyen, Lianwen Sun, Virginie Mariot, Julie Dumonceaux, Jennifer E. Morgan, Paul Gissen, George Dickso, Francesco Muntoni

Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy
Background
Spinal muscular atrophy (SMA) is caused by genetic defects in the survival motor neuron 1 (SMN1 ) gene that lead to SMN deficiency. Different SMN‐restoring therapies substantially prolong survival and function in transgenic mice of SMA. However, these therapies do not entirely prevent muscle atrophy and restore function completely. To further improve the outcome, we explored the potential of a combinatorial therapy by modulating SMN production and muscle‐enhancing approach as a novel therapeutic strategy for SMA.
Methods
The experiments were performed in a mouse model of severe SMA. A previously reported 25‐mer morpholino antisense oligomer PMO25 was used to restore SMN expression. The adeno‐associated virus‐mediated expression of myostatin propeptide was used to block the myostatin pathway. Newborn SMA mice were treated with a single subcutaneous injection of 40 μg/g (therapeutic dose) or 10 μg/g (low‐dose) PMO25 on its own or together with systemic delivery of a single dose of adeno‐associated virus‐mediated expression of myostatin propeptide. The multiple effects of myostatin inhibition on survival, skeletal muscle phenotype, motor function, neuromuscular junction maturation, and proprioceptive afferences were evaluated.
Results
We show that myostatin inhibition acts synergistically with SMN‐restoring antisense therapy in SMA mice treated with the higher therapeutic dose PMO25 (40 μg/g), by increasing not only body weight (21% increase in male mice at Day 40), muscle mass (38% increase), and fibre size (35% increase in tibialis anterior muscle in 3 month female SMA mice), but also motor function and physical performance as measured in hanging wire test (two‐fold increase in time score) and treadmill exercise test (two‐fold increase in running distance). In SMA mice treated with low‐dose PMO25 (10 μg/g), the early application of myostatin inhibition prolongs survival (40% increase), improves neuromuscular junction maturation (50% increase) and innervation (30% increase), and increases both the size of sensory neurons in dorsal root ganglia (60% increase) and the preservation of proprioceptive synapses in the spinal cord (30% increase).
Conclusions
These data suggest that myostatin inhibition, in addition to the well‐known effect on muscle mass, can also positively influence the sensory neural circuits that may enhance motor neurons function. While the availability of the antisense drug Spinraza for SMA and other SMN‐enhancing therapies has provided unprecedented improvement in SMA patients, there are still unmet needs in these patients. Our study provides further rationale for considering myostatin inhibitors as a therapeutic intervention in SMA patients, in combination with SMN‐restoring drugs.

Zhou, H., Meng, J., Malerba, A., Catapano, F., Sintusek, P., Jarmin, S., Feng, L., Lu‐Nguyen, N., Sun, L., Mariot, V., Dumonceaux, J., Morgan, J. E., Gissen, P., Dickson, G., and Muntoni, F. (2020) Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy, Journal of Cachexia, Sarcopenia and Muscle, 11, 768– 782. https://doi.org/10.1002/jcsm.12542.

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     Article first published online:  27 February 2020

Domiziana Costamagna, Robin Duelen, Fabio Penna, Detlef Neumann, Paola Costelli, Maurilio Sampaolesi

Interleukin‐4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma‐bearing mice
Background
Anorexia, body wasting, inflammation, muscle, and adipose tissue loss are hallmarks of cancer cachexia, a syndrome that affects the majority of cancer patients, impairing their ability to endure chemotherapeutic therapies and reducing their lifespan. In the last 10 years, alterations of protein turnover and impairment of adult myogenesis have been proposed as major contributing factors.
Methods
Muscle stem cells, including satellite cells, mesoangioblasts, and fibroadipogenic progenitors, were isolated and characterized from C26 colon carcinoma‐bearing (C26) mice. Circulating levels of interleukin‐4/13 (IL4/IL13) were analysed by ELISA, and the effects of IL4 on muscle mass and function, protein synthesis, muscle regeneration, and myogenic progenitor cell number were analysed at both functional (treadmill and grip test) and molecular levels (qRT–PCR, immunofluorescence analysis, surface sensing of translation, and western blot). The Kaplan–Meier test was used to analyse the survival curve of IL4‐treated and IL4‐untreated C26 mice.
Results
The administration of IL4 to C26 mice rescued muscle mass by increasing protein synthesis. The IL4 treatment improved performances and prolonged survival of C26 mice. IL4 administration re‐established both number and function of satellite cells and fibroadipogenic progenitors without affecting mesoangioblasts in C26 mice, rescuing myogenesis. Upon IL4 treatment, a high number of cytotoxic lymphocytes and type II macrophages were observed with a subsequent increase in necrotic areas of C26 tumours.
Conclusions
The results here presented shed new light on IL4 signalling during muscle wasting and early stages of muscle regeneration that explain the beneficial effect observed in IL4‐treated C26 mice. These findings might aid to develop therapeutic approaches to improve mobility and quality of life in cachectic patients.

Costamagna, D., Duelen, R., Penna, F., Neumann, D., Costelli, P., and Sampaolesi, M. (2020) Interleukin‐4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma‐bearing mice, Journal of Cachexia, Sarcopenia and Muscle, 11, 783– 801. https://doi.org/10.1002/jcsm.12539.

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     Article first published online:  10 March 2020

Maurizio Vitadello, Matteo Sorge, Elena Percivalle, Elena Germinario, Daniela Danieli‐Betto, Emilia Turco, Guido Tarone, Mara Brancaccio, Luisa Gorza

Loss of melusin is a novel, neuronal NO synthase/FoxO3‐independent master switch of unloading‐induced muscle atrophy
Background
Unloading/disuse induces skeletal muscle atrophy in bedridden patients and aged people, who cannot prevent it by means of exercise. Because interventions against known atrophy initiators, such as oxidative stress and neuronal NO synthase (nNOS) redistribution, are only partially effective, we investigated the involvement of melusin, a muscle‐specific integrin‐associated protein and a recognized regulator of protein kinases and mechanotransduction in cardiomyocytes.
Methods
Muscle atrophy was induced in the rat soleus by tail suspension and in the human vastus lateralis by bed rest. Melusin expression was investigated at the protein and transcript level and after treatment of tail‐suspended rats with atrophy initiator inhibitors. Myofiber size, sarcolemmal nNOS activity, FoxO3 myonuclear localization, and myofiber carbonylation of the unloaded rat soleus were studied after in vivo melusin replacement by cDNA electroporation, and muscle force, myofiber size, and atrogene expression after adeno‐associated virus infection. In vivo interference of exogenous melusin with dominant‐negative kinases and other atrophy attenuators (Grp94 cDNA; 7‐nitroindazole) on size of unloaded rat myofibers was also explored.
Results
Unloading/disuse reduced muscle melusin protein levels to about 50%, already after 6 h in the tail‐suspended rat (P < 0.001), and to about 35% after 8 day bed rest in humans (P < 0.05). In the unloaded rat, melusin loss occurred despite of the maintenance of β1D integrin levels and was not abolished by treatments inhibiting mitochondrial oxidative stress, or nNOS activity and redistribution. Expression of exogenous melusin by cDNA transfection attenuated atrophy of 7 day unloaded rat myofibers (−31%), compared with controls (−48%, P = 0.001), without hampering the decrease in sarcolemmal nNOS activity and the increase in myonuclear FoxO3 and carbonylated myofibers. Infection with melusin‐expressing adeno‐associated virus ameliorated contractile properties of 7 day unloaded muscles (P ≤ 0.05) and relieved myofiber atrophy (−33%) by reducing Atrogin‐1 and MurF‐1 transcripts (P ≤ 0.002), despite of a two‐fold increase in FoxO3 protein levels (P = 0.03). Atrophy attenuation by exogenous melusin did not result from rescue of Akt, ERK, or focal adhesion kinase activity, because it persisted after co‐transfection with dominant‐negative kinase forms (P < 0.01). Conversely, melusin cDNA transfection, combined with 7‐nitroindazole treatment or with cDNA transfection of the nNOS‐interacting chaperone Grp94, abolished 7 day unloaded myofiber atrophy.
Conclusions
Disuse/unloading‐induced loss of melusin is an early event in muscle atrophy which occurs independently from mitochondrial oxidative stress, nNOS redistribution, and FoxO3 activation. Only preservation of melusin levels and sarcolemmal nNOS localization fully prevented muscle mass loss, demonstrating that both of them act as independent, but complementary, master switches of muscle disuse atrophy.

Vitadello, M., Sorge, M., Percivalle, E., Germinario, E., Danieli‐Betto, D., Turco, E., Tarone, G., Brancaccio, M., and Gorza, L. (2020) Loss of melusin is a novel, neuronal NO synthase/FoxO3‐independent master switch of unloading‐induced muscle atrophy, Journal of Cachexia, Sarcopenia and Muscle, 11, 802– 819. https://doi.org/10.1002/jcsm.12546.

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     Article first published online:  10 February 2020

Rachel L. Nosacka, Andrea E. Delitto, Dan Delitto, Rohan Patel, Sarah M. Judge, Jose G. Trevino, Andrew R. Judge

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle
Background
Cancer cachexia is a life‐threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre‐clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre‐clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient‐derived xenograft (PDX) mice.
Methods
To create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice.
Results
Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome‐wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up‐regulated in the DIA were enriched for extracellular matrix protein‐encoding genes and genes related to the inflammatory response, while down‐regulated genes were enriched for mitochondria related protein‐encoding genes. Conversely, the TA showed up‐regulation of canonical atrophy‐associated pathways such as ubiquitin‐mediated protein degradation and apoptosis, and down‐regulation of genes encoding extracellular matrix proteins.
Conclusions
These data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.

Huang, C.‐Y., Yang, Y.‐C., Chen, T.‐C., Chen, J.‐R., Chen, Y.‐J., Wu, M.‐H., Jan, Y.‐T., Chang, C.‐L., and Lee, J. ( 2020) Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer, Journal of Cachexia, Sarcopenia and Muscle, 11, 534– 546. https://doi.org/10.1002/jcsm.12524.

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     Article first published online:  23 February 2020

Daniele Capitanio, Manuela Moriggi, Enrica Torretta, Pietro Barbacini, Sara De Palma, Agnese Viganò, Hanns Lochmüller, Francesco Muntoni, Alessandra Ferlini, Marina Mora, Cecilia Gelfi

Caveolin‐3 deficiency associated with the dystrophy P104L mutation impairs skeletal muscle mitochondrial form and function
Background
Caveolin‐3 (Cav3) is the principal structural component of caveolae in skeletal muscle. Dominant pathogenic mutations in the Cav3 gene, such as the Limb Girdle Muscular Dystrophy‐1C (LGMD1C) P104L mutation, result in substantial loss of Cav3 and myopathic changes characterized by muscle weakness and wasting. We hypothesize such myopathy may also be associated with disturbances in mitochondrial biology. Herein, we report studies assessing the effects of Cav3 deficiency on mitochondrial form and function in skeletal muscle cells.
Methods
L6 myoblasts were stably transfected with Cav3P104L or expression of native Cav3 repressed by shRNA or CRISPR/Cas9 genome editing prior to performing fixed/live cell imaging of mitochondrial morphology, subcellular fractionation and immunoblotting, or analysis of real time mitochondrial respiration. Skeletal muscle from wild‐type and Cav3−/− mice was processed for analysis of mitochondrial proteins by immunoblotting.
Results
Caveolin‐3 was detected in mitochondrial‐enriched membranes isolated from mouse gastrocnemius muscle and L6 myoblasts. Expression of Cav3P104L in L6 myoblasts led to its targeting to the Golgi and loss of native Cav3 (>95%), including that associated with mitochondrial membranes. Cav3P104L reduced mitochondrial mass and induced fragmentation of the mitochondrial network that was associated with significant loss of proteins involved in mitochondrial biogenesis, respiration, morphology, and redox function [i.e. PGC1α, succinate dehyrdogenase (SDHA), ANT1, MFN2, OPA1, and MnSOD). Furthermore, Cav3P104L myoblasts exhibited increased mitochondrial cholesterol and loss of cardiolipin. Consistent with these changes, Cav3P104L expression reduced mitochondrial respiratory capacity and increased myocellular superoxide production. These morphological, biochemical, and functional mitochondrial changes were phenocopied in myoblasts in which Cav3 had been silenced/knocked‐out using shRNA or CRISPR. Reduced mitochondrial mass, PGC1α, SDHA, ANT1, and MnSOD were also demonstrable in Cav3−/− mouse gastrocnemius. Strikingly, Cav3 re‐expression in Cav3KO myoblasts restored its mitochondrial association and facilitated reformation of a tubular mitochondrial network. Significantly, re‐expression also mitigated changes in mitochondrial superoxide, cholesterol, and cardiolipin content and recovered cellular respiratory capacity.
Conclusions
Our results identify Cav3 as an important regulator of mitochondrial homeostasis and reveal that Cav3 deficiency in muscle cells associated with the Cav3P104L mutation invokes major disturbances in mitochondrial respiration and energy status that may contribute to the pathology of LGMD1C.

Shah, D. S., Nisr, R. B., Stretton, C., Krasteva‐Christ, G., and Hundal, H. S. (2020) Caveolin‐3 deficiency associated with the dystrophy P104L mutation impairs skeletal muscle mitochondrial form and function, Journal of Cachexia, Sarcopenia and Muscle, 11, 838– 858. https://doi.org/10.1002/jcsm.12541.

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