Article first published online:  27 February 2019

Miguel S. Conceição, Carlos Ugrinowitsch

Exercise with blood flow restriction: an effective alternative for the non-pharmaceutical treatment for muscle wasting
Significant muscle wasting is generally experienced by ill and bed rest patients and older people. Muscle wasting leads to significant decrements in muscle strength, cardiorespiratory, and functional capacity, which increase mortality rates. As a consequence, different interventions have been tested to minimize muscle wasting. In this regard, blood flow restriction (BFR) has been used as a novel therapeutic approach to mitigate the burden associated with muscle waste conditions. Evidence has shown that BFR per se can counteract muscle wasting during immobilization or bed rest. Moreover, BFR has also been applied while performing low intensity resistance and endurance exercises and produced increases in muscle strength and mass. Endurance training with BFR has also been proved to increase cardiorespiratory fitness. Thus, frail patients can benefit from exercising with BFR due to the lower cardiovascular and join stress compared with traditional high intensity exercises. Therefore, low intensity resistance and endurance training combined with BFR may be considered as a novel and attractive intervention to counteract muscle wasting and to decrease the burden associated with this condition.

 

Conceição, M. S., and Ugrinowitsch, C. ( 2019) Exercise with blood flow restriction: an effective alternative for the non‐pharmaceutical
treatment for muscle wasting. Journal of Cachexia, Sarcopenia and Muscle, 10: 257– 262. https://doi.org/10.1002/jcsm.12397. 

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     Article first published online:  22 February 2019

Cecilia Minaglia, Chiara Giannotti, Virginia Boccardi, Patrizia Mecocci, Gianluca Serafini, Patrizio Odetti, Fiammetta Monacelli

Cachexia and advanced dementia
Cachexia is a complex metabolic process that is associated with several end-stage organ diseases. It is known to be also associated with advanced dementia, although the pathophysiologic mechanisms are still largely unknown. The present narrative review is aimed at presenting recent insights concerning the pathophysiology of weight loss and wasting syndrome in dementia, the putative mechanisms involved in the dysregulation of energy balance, and the interplay among the chronic clinical conditions of sarcopenia, malnutrition, and frailty in the elderly. We discuss the clinical implications of these new insights, with particular attention to the challenging question of nutritional needs in advanced dementia and the utility of tube feeding in order to optimize the management of end-stage dementia.

Minaglia, C., Giannotti, C., Boccardi, V., Mecocci, P., Serafini, G., Odetti, P., and Monacelli, F. ( 2019) Cachexia and advanced
dementia. Journal of Cachexia, Sarcopenia and Muscle, 10: 263– 277. https://doi.org/10.1002/jcsm.12380.

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     Article first published online:  06 March 2019 

Robinson Ramírez-Vélez, Jorge Enrique Correa-Bautista, Antonio García-Hermoso, Carlos Alberto, Cano Mikel Izquierdo

Reference values for handgrip strength and their association with intrinsic capacity domains among older adults
Objective
The purposes of this study were three-fold: (i) to describe handgrip strength in older individuals aged =60 years in Colombia; (ii) to identify sex-specific and age-specific muscle weakness cut-off points in older adults; and (iii) to determine the odds of adverse events for each of the intrinsic capacity domains for individuals with handgrip strength greater than the muscle weakness cut-off points, as compared with their weaker counterparts.
Methods
A cross-sectional study was conducted in Colombia, among 5237 older adults aged =60 years old (58.5% women, 70.5 ± 7.8 years), according to ‘SABE Survey 2015’. Handgrip strength data were obtained with a Takei dynamometer. Sociodemographic variables, five domains of intrinsic capacity (i.e. locomotion, vitality, cognition, psychological, and sensory), and medical conditions were assessed and analyzed. Adjustments variables were age, ethnicity, socio-economic status, urbanicity, body mass index, smoking status, alcohol intake, drug use, physical activity, and co-morbid chronic diseases. Sex-stratified analyses were conducted with logistic regression models.
Results
Handgrip strength was greater among men than among women (26.7 ± 8.5 vs. 16.7 ± 5.7 kg, respectively, P < 0.001) at all ages. Weak handgrip strength cut-off points ranged from 17.4 to 8.6 and from 10.1 to 4.9 in men and women, respectively. Overall, participants with optimal handgrip strength had better intrinsic capacity [in men, odds ratio (OR) = 0.62, 95% confidence interval (CI) 0.53 to 0.71; P < 0.001; and in women, OR = 0.79, 95% CI 0.68 to 0.92; P = 0.002] than their weaker counterparts. Also, men with optimal handgrip strength had a lower risk of hospitalization (OR = 0.47, 95% CI 0.29 to 0.78; P = 0.004) than their weaker counterparts.
Conclusions
This study is the first to describe handgrip strength values and cut-off points for muscle weakness among a nationally representative sample of Colombian older adults by age and sex. After categorizing older adults as weak or not weak based on the handgrip cut-off points, non-weakness was associated with a decreased odds of intrinsic capacity impairments. These cut-off points may be good candidates for clinical assessment of risks to physical and mental health in older Colombian adults.

Ramírez‐Vélez, R., Correa‐Bautista, J. E., García‐Hermoso, A., Cano, C. A., and Izquierdo, M. ( 2019) Reference values for handgrip strength and their association with intrinsic capacity domains among older adults. Journal of Cachexia, Sarcopenia and Muscle, 10: 278–286. https://doi.org/10.1002/jcsm.12373.

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     Article first published online:  04 March 2019 

Haritz Arrieta, Cyril Astrugue, Sophie Regueme Jessica Durrieu, Aline Maillard, Alban Rieger, Eric Terrebonne, Christophe Laurent, Brigitte Maget, Véronique Servent, Sandrine Lavau-Denès, Jérôme Dauba, Marianne Fonck, Rodolphe Thiébaut, Isabelle Bourdel-Marchasson

Effects of a physical activity programme to prevent physical performance decline in onco-geriatric patients: a randomized multicentre trial
Background
Older adults with cancer experience negative long-term functional effects of both cancer and treatments. Exercise may minimize their age-related and cancer-related functional decline.
Methods
We conducted a multicentre open-label 12 month randomized clinical trial with two parallel arms including participants aged =70 years with lymphoma or carcinoma requiring curative treatment. The study started at the beginning of any phase of cancer treatment (surgery, chemotherapy, or radiotherapy). The usual care group (UCG) received the current national recommendations in physical activity (a guideline without specific counselling). The intervention group (IG) received 1 year phoned physical activity advice individually adapted to physical assessment (twice a month during the first 6 months and then monthly). The primary outcome was the proportion of subjects with a 1 year decreased short physical performance battery (SPPB) score of 1 point or more. Physical, cognitive, and clinical secondary outcomes were also investigated.
Results
We allocated 301 participants (age 76.7 ± 5.0, female 60.6%) to each group. At baseline, the median SPPB was 10/12 in both groups. Breast was the most frequent tumour site (35.7%). After 1 year, 14.0% of participants in the UCG and 18.7% in the IG had a decrease in SPPB score of 1 point or more (P = 0.772). At 2 years, there was no difference in SPPB, gait speed, International Physical Activity Questionnaire score, and verbal fluency. Subgroup analyses after 2 years showed a decline in SPPB for 29.8% of UCG and 5.0% of IG breast cancer participants (P = 0.006), in 21.7% of UCG and 6.2% of IG female participants (P = 0.019), and in 24.5% of UCG and 11.1% of IG normal nutritional status participants (P = 0.009). Falls, hospitalization, institutionalization, and death rates were similar in both groups.
Conclusions
Personalized phoned physical activity advice had not reduced functional decline at 1 year but provided preliminary evidence that may prevent physical performance decline at 2 years in older adults with breast cancer.

Arrieta, H., Astrugue, C., Regueme, S., Durrieu, J., Maillard, A., Rieger, A., Terrebonne, E., Laurent, C., Maget, B., Servent, V., Lavau-Denès, S., Dauba, J., Fonck, M., Thiébaut, R., and Bourdel-Marchasson, I. (2019) Effects of a physical activity programme to prevent physical performance decline in onco-geriatric patients: a randomized multicentre trial. Journal of Cachexia, Sarcopenia and Muscle, 10: 287– 297. https://doi.org/10.1002/jcsm.12382.

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     Article first published online:  07 March 2019 

Dominique S.M. ten Haaf, Thijs M.H. Eijsvogels, Coen C.W.G. Bongers, Astrid M.H. Horstman, Silvie Timmers, Lisette C.P.G.M. de Groot, Maria T.E. Hopman

Protein supplementation improves lean body mass in physically active older adults: a randomized placebo-controlled trial

Background
An inadequate protein intake may offset the muscle protein synthetic response after physical activity, reducing the possible benefits of an active lifestyle for muscle mass. We examined the effects of 12 weeks of daily protein supplementation on lean body mass, muscle strength, and physical performance in physically active older adults with a low habitual protein intake (<1.0 g/kg/day).
Methods
A randomized double-blinded controlled trial was performed among 116 physically active older adults [age 69 (interquartile range: 67–73) years, 82% male] who were training for a 4 day walking event of 30, 40, or 50 km/day. Participants were randomly allocated to either 31 g of milk protein or iso-caloric placebo supplementation for 12 weeks. Body composition (dual-energy X-ray absorptiometry), strength (isometric leg extension and grip strength), quadriceps contractile function, and physical performance [Short Physical Performance Battery, Timed Up-and-Go test, and cardiorespiratory fitness (Åstrand–Rhyming submaximal exercise test)] were measured at baseline and after 12 weeks. We assessed vitamin D status and markers of muscle damage and renal function in blood and urine samples before and after intervention.
Results
A larger increase in relative lean body mass was observed in the protein vs. placebo group (?0.93 ± 1.22% vs. ?0.44 ± 1.40%, PInteraction = 0.046). Absolute and relative fat mass decreased more in the protein group than in the placebo group (?-0.90 ± 1.22 kg vs. ?-0.31 ± 1.28 kg, PInteraction = 0.013 and ?-0.92 ± 1.19% vs. ?-0.39 ± 1.36%, PInteraction = 0.029, respectively). Strength and contractile function did not change in both groups. Gait speed, chair-rise ability, Timed Up-and-Go, and cardiorespiratory fitness improved in both groups (P < 0.001), but no between-group differences were observed. Serum urea increased in the protein group, whereas no changes were observed in the placebo group (PInteraction < 0.001). No between-group differences were observed for vitamin D status, muscle damage, and renal function markers.
Conclusions
In physically active older adults with relatively low habitual dietary protein consumption, an improvement in physical performance, an increase in lean body mass, and a decrease in fat mass were observed after walking exercise training. A larger increase in relative lean body mass and larger reduction in fat mass were observed in participants receiving 12 weeks of daily protein supplementation compared with controls, whereas this was not accompanied by differences in improvements between groups in muscle strength and physical performance.

ten Haaf, D. S. M., Eijsvogels, T. M. H., Bongers, C. C. W. G., Horstman, A. M. H., Timmers, S., de Groot, L. C. P. G. M., and Hopman, M. T. E. (2019) Protein supplementation improves lean body mass in physically active older adults: a randomized placebo-controlled trial. Journal of Cachexia, Sarcopenia and Muscle, 10: 298– 310. https://doi.org/10.1002/jcsm.12394.

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     Article first published online:  18 January 2019

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

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

Kneppers, A. E. M., Haast, R. A. M., Langen, R. C. J., Verdijk, L. B., Leermakers, P. A., Gosker, H. R., van Loon, L. J. C., Lainscak, M., and Schols, A. M. W. J. (2019) Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis. Journal of Cachexia, Sarcopenia and Muscle, 10: 311– 322. https://doi.org/10.1002/jcsm.12370.

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     Article first published online:  29 January 2019

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

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

Aniort, J., Stella, A., Philipponnet, C., Poyet, A., Polge, C., Claustre, A., Combaret, L., Béchet, D., Attaix, D., Boisgard, S., Filaire, M., Rosset, E., Burlet‐Schiltz, O., Heng, A.‐E., and Taillandier, D. (2019) Muscle wasting in patients with end‐stage renal disease or early‐stage lung cancer: common mechanisms at work. Journal of Cachexia, Sarcopenia and Muscle, 10: 323– 337. https://doi.org/10.1002/jcsm.12376.

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     Article first published online:  19 February 2019

Susan L. Ziolkowski, Jin Long, Joshua F. Baker, Glenn M. Chertow, Mary B. Leonard

Relative sarcopenia and mortality and the modifying effects of chronic kidney disease and adiposity
Background
Conventional definitions of sarcopenia based on lean mass may fail to capture low lean mass relative to higher fat mass, that is, relative sarcopenia. The objective of this study is to determine the associations of sarcopenia and relative sarcopenia with mortality independent of co-morbidities, and whether chronic kidney disease (CKD) and adiposity alter these associations.
Methods
Dual energy X-ray absorptiometry-derived appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2) were assessed in 14 850 National Health and Nutrition Examination Survey participants from 1999 to 2006 and were linked to death certificate data in the National Death Index with follow-up through 2011. Sarcopenia was defined using sex-specific and race/ethnicity-specific standard deviation scores compared with young adults (T-scores) as an ALMI T-score < -2 and relative sarcopenia as fat-adjusted ALMI (ALMIFMI) T-score < -2. Glomerular filtration rate (GFR) was estimated using creatinine-based (eGFRCr) and cystatin C-based (eGFRCys) regression equations.
Results
Three (3.0) per cent of National Health and Nutrition Examination Survey participants met criteria for sarcopenia and 8.7% met criteria for relative sarcopenia. Sarcopenia and relative sarcopenia were independently associated with mortality (HR sarcopenia 2.20, 95% CI 1.69 to 2.86; HR relative sarcopenia 1.60, 95% CI 1.31 to 1.96). The corresponding population attributable risks were 5.2% (95% CI 3.4% to 6.4%) and 8.4% (95% CI 4.8% to 11.2%), respectively. Relative sarcopenia remained significantly associated with mortality (HR 1.32, 95% CI 1.08 to 1.61) when limited to the subset who did not meet the criteria for sarcopenia. The risk of mortality associated with relative sarcopenia was attenuated among persons with higher FMI (P for interaction <0.01) and was not affected by CKD status for either sarcopenia or relative sarcopenia.
Conclusions
Sarcopenia and relative sarcopenia are significantly associated with mortality regardless of CKD status. Relative sarcopenia is nearly three-fold more prevalent amplifying its associated mortality risk at the population level. The association between relative sarcopenia and mortality is attenuated in persons with higher FMI.

Ziolkowski, S. L., Long, J., Baker, J. F., Chertow, G. M., and Leonard, M. B. (2019) Relative sarcopenia and mortality and the modifying effects of chronic kidney disease and adiposity. Journal of Cachexia, Sarcopenia and Muscle, 10: 338– 346. https://doi.org/10.1002/jcsm.12396.

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     Article first published online:  21 February 2019

Atsushi Hiraoka, Hirofumi Izumoto, Hidetaro Ueki, Takeaki Yoshino, Toshihiko Aibiki, Tomonari Okudaira, Hiroka Yamago, Yoshifumi Suga, Ryuichiro Iwasaki, Hideomi Tomida, Kenichiro Mori, Hideki Miyata, Eiji Tsubouchi, Masato Kishida, Tomoyuki Ninomiya, Masashi Hirooka, Masanori Abe, Bunzo Matsuura, Yoichi Hiasa, Kojiro Michitaka

Easy surveillance of muscle volume decline in chronic liver disease patients using finger-circle (yubi-wakka) test
Background
Muscle atrophy (MA) and muscle strength decline are important clinical features in chronic liver disease (CLD) patients. An easy to perform MA screening method without need for special equipment would be helpful. We evaluated the usefulness of the previously reported finger-circle test as screening for MA in CLD patients.
Methods
We retrospectively enrolled 358 Japanese CLD outpatients (70.8 ± 10.2 years, male/female = 234/124) who had undergone a computed tomography examination from December 2017 to March 2018, of whom 137 had chronic hepatitis, 169 had liver cirrhosis Child–Pugh A, and 52 had liver cirrhosis Child–Pugh B/C. Bilateral psoas muscle area at the middle of the third lumber vertebra (L3) was evaluated with computed tomography findings, which was performed as a screening of hepatocellular carcinoma, using a previously reported parameter for MA [psoas index (PI): total psoas muscle area (cm2)/height (m)2] [mean PI ± standard deviation (SD) of male patients: 6.50 ± 1.13 cm2/m2 and those of female patients: 4.30 ± 0.90 cm2/m2]. We then evaluated the correlation between MA and finger-circle test results in these patients.
Results
The mean PI values for finger-circle test results Bigger, Just-fits, and Smaller were 5.64 ± 1.34, 5.00 ± 1.25, and 4.83 ± 1.46 cm2/m2, respectively, in male patients (P < 0.001) and 4.31 ± 1.06, 3.93 ± 0.97, and 3.42 ± 0.94 cm2/m2, respectively, in female patients (P = 0.001). We found that a finger-circle test result in male patients other than Bigger (Just-fits and Smaller) predicted a decline in psoas muscle area of L3 to PI 5.25 cm2/m2 (sensitivity/specificity 0.619/0.667, area under the curve 0.654, 95% confidence interval 0.583–0.724), which was approximately mean minus 1 SD (5.37 cm2/m2). On the other hand, a Smaller test result in female patients predicted a decline in psoas muscle area of L3 to PI 3.33 cm2/m2 (sensitivity/specificity 0.740/0.583, area under the curve 0.698, 95% confidence interval 0.583–0.813), approximately mean minus 1 SD (3.40 cm2/m2).
Conclusions
The finger-circle test is an easy to perform and effective screening method for predicting earlier stage of MA in CLD patients without the need for special equipment.

Shen, S., Liao, Q., Liu, J., Pan, R., Lee, S. M.-Y., and Lin, L. (2019) Myricanol rescues dexamethasone-induced muscle dysfunction via a sirtuin 1-dependent mechanism. Journal of Cachexia, Sarcopenia and Muscle, 10: 347– 354. https://doi.org/10.1002/jcsm.12392.

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     Article first published online:  30 January 2019

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

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

Lin, J.‐Z., Liang, J.‐J., Ma, J.‐D., Li, Q.‐H., Mo, Y.‐Q., Cheng, W.‐M., He, X.‐L., Li, N., Cao, M.‐H., Xu, D., and Dai, L. (2019) Myopenia is associated with joint damage in rheumatoid arthritis: a cross‐sectional study. Journal of Cachexia, Sarcopenia and Muscle, 10: 355– 367. https://doi.org/10.1002/jcsm.12381.

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     Article first published online:  04 February 2019

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

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

Basile, D., Parnofiello, A., Vitale, M. G., Cortiula, F., Gerratana, L., Fanotto, V., Lisanti, C., Pelizzari, G., Ongaro, E., Bartoletti, M., Garattini, S. K., Andreotti, V. J., Bacco, A., Iacono, D., Bonotto, M., Casagrande, M., Ermacora, P., Puglisi, F., Pella, N., Fasola, G., Aprile, G., and Cardellino, G. G. (2019) The IMPACT study: early loss of skeletal muscle mass in advanced pancreatic cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 10: 368377. https://doi.org/10.1002/jcsm.12368.

ABSTRACT | PDF |

 

     Article first published online:  21 January 2019

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

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

Zhu, X., Burfeind, K. G., Michaelis, K. A., Braun, T. P., Olson, B., Pelz, K. R., Morgan, T. K., and Marks, D. L. (2019) MyD88 signalling is critical in the development of pancreatic cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle, 10: 378-390. https://doi.org/10.1002/jcsm.12377.

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     Article first published online:  30 January 2019

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

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

Li, Z., Cai, B., Abdalla, B. A., Zhu, X., Zheng, M., Han, P., Nie, Q., and Zhang, X. (2019) LncIRS1 controls muscle atrophy via sponging miR‐15 family to activate IGF1‐PI3K/AKT pathway. Journal of Cachexia, Sarcopenia and Muscle, 10: 391-410. https://doi.org/10.1002/jcsm.12374.

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     Article first published online:  01 February 2019

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

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

Ahn, B., Ranjit, R., Premkumar, P., Pharaoh, G., Piekarz, K. M., Matsuzaki, S., Claflin, D. R., Riddle, K., Judge, J., Bhaskaran, S., Satara Natarajan, K., Barboza, E., Wronowski, B., Kinter, M., Humphries, K. M., Griffin, T. M., Freeman, W. M., Richardson, A., Brooks, S. V., and Van Remmen, H. (2019) Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching. Journal of Cachexia, Sarcopenia and Muscle, 10: 411-428. https://doi.org/10.1002/jcsm.12375.

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     Article first published online:  21 February 2019

Shengnan Shen, Qiwen Liao, Jingxin Liu, Ruile Pan, Simon Ming-Yuen Lee, Ligen Lin

Myricanol rescues dexamethasone-induced muscle dysfunction via a sirtuin 1-dependent mechanism
Background
Muscle atrophy and weakness are adverse effects of high dose or the sustained usage of glucocorticoids. Loss of mitochondria and degradation of protein are highly correlated with muscle dysfunction. The deacetylase sirtuin 1 (SIRT1) plays a vital role in muscle remodelling. The current study was designed to identify myricanol as a SIRT1 activator, which could protect skeletal muscle against dexamethasone-induced wasting.
Methods
The dexamethasone-induced atrophy in C2C12 myotubes was evaluated by expression of myosin heavy chain, muscle atrophy F-box (atrogin-1), and muscle ring finger 1 (MuRF1), using western blots. The mitochondrial content and oxygen consumption were assessed by MitoTracker staining and extracellular flux analysis, respectively. Muscle dysfunction was established in male C57BL/6 mice (8–10 weeks old, n = 6) treated with a relatively high dose of dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, forced swimming capacity, muscle weight, and muscle histology were assessed. The expression of proteolysis-related, autophagy-related, apoptosis-related, and mitochondria-related proteins was analysed by western blots or immunoprecipitation.
Results
Myricanol (10 µM) was found to rescue dexamethasone-induced muscle atrophy and dysfunction in C2C12 myotubes, indicated by increased expression of myosin heavy chain (0.33 ± 0.14 vs. 0.89 ± 0.21, *P < 0.05), decreased expression of atrogin-1 (2.31 ± 0.67 vs. 1.53 ± 0.25, *P < 0.05) and MuRF1 (1.55 ± 0.08 vs. 0.99 ± 0.12, **P < 0.01), and elevated ATP production (3.83 ± 0.46 vs. 5.84 ± 0.79 nM/mg protein, **P < 0.01), mitochondrial content (68.12 ± 10.07% vs. 116.38 ± 5.12%, *P < 0.05), and mitochondrial oxygen consumption (166.59 ± 22.89 vs. 223.77 ± 22.59 pmol/min, **P < 0.01). Myricanol directly binds and activates SIRT1, with binding energy of -5.87 kcal/mol. Through activating SIRT1 deacetylation, myricanol inhibits forkhead box O 3a transcriptional activity to reduce protein degradation, induces autophagy to enhance degraded protein clearance, and increases peroxisome proliferator-activated receptor ? coactivator-1a activity to promote mitochondrial biogenesis. In dexamethasone-induced muscle wasting C57BL/6 mice, 5 mg/kg myricanol treatment reduces the loss of muscle mass; the percentages of quadriceps and gastrocnemius muscle in myricanol-treated mice are 1.36 ± 0.02% and 0.87 ± 0.08%, respectively (cf. 1.18 ± 0.06% and 0.78 ± 0.05% in dexamethasone-treated mice, respectively). Myricanol also rescues dexamethasone-induced muscle weakness, indicated by improved grip strength (70.90 ± 4.59 vs. 120.58 ± 7.93 g, **P < 0.01) and prolonged swimming exhaustive time (48.80 ± 11.43 vs. 83.75 ± 15.19 s, **P < 0.01). Myricanol prevents dexamethasone-induced muscle atrophy and weakness by activating SIRT1, to reduce muscle protein degradation, enhance autophagy, and promote mitochondrial biogenesis and function in mice.
Conclusions
Myricanol ameliorates dexamethasone-induced skeletal muscle wasting by activating SIRT1, which might be developed as a therapeutic agent for treatment of muscle atrophy and weakness.

Shen, S., Liao, Q., Liu, J., Pan, R., Lee, S. M.-Y., and Lin, L. (2019) Myricanol rescues dexamethasone-induced muscle dysfunction via a sirtuin 1-dependent mechanism. Journal of Cachexia, Sarcopenia and Muscle, 10: 429-444. https://doi.org/10.1002/jcsm.12393.

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     Article first published online:  28 March 2019 

Ilanna Marques Gomes da Rocha, Aline Marcadenti, Galtieri Otávio Cunha de Medeiros, Ricardo Andrade Bezerra,
Juliana Florinda de Mendonça Rego, Maria Cristina Gonzalez, Ana Paula Trussardi Fayh

Is cachexia associated with chemotherapy toxicities in gastrointestinal cancer patients? A prospective study

Background
Chemotherapy is an effective treatment with good clinical response in patients with cancer. However, it can cause exacerbated toxicities in patients and consequently change the course of treatment. Some factors may interfere with this toxicity such as body composition, especially in gastrointestinal cancer. The aim of this study was to evaluate the effects of body composition, nutritional status, and functional capacity scale in predicting the occurrence of toxicities in gastrointestinal cancer patients during chemotherapy treatment.
Methods
This is a prospective study with gastrointestinal cancer patients at the beginning of chemotherapy treatment. Sarcopenia and muscle attenuation were assessed using the skeletal muscle index from computerized tomography by measuring cross‐sectional areas of the L3 tissue (cm2/m2). Cachexia was graded according to involuntary weight loss associated with sarcopenia. Nutritional status was assessed by using anthropometric evaluation and Patient‐Generated Subjective Global Assessment. Functional capacity was evaluated by handgrip strength and Eastern Cooperative Oncology Group (ECOG) Performance Status scale. Haematological gastrointestinal and dose‐limiting toxicities (DLTs) were defined according to National Cancer Institute Common Toxicity Criteria. The associations among sarcopenia, cachexia, nutritional status, and functional capacity with DLT were assessed by univariate and multivariate Cox regression model.
Results
A total of 60 patients were evaluated (55% male, 60.9 ± 14.0 years) and followed up for a mean of 55 days. Most patients had normal weight (44.2%) and good ECOG Performance Status (≤1) at baseline (78%). During the chemotherapy period, the most prevalent toxicities were diarrhoea, nausea, and anorexia, but the presence of DLT was similar between cycles (P > 0.05). Cachexia was associated with a higher toxicity manifested by diarrhoea (P = 0.02), nausea (P = 0.02), and anorexia (P < 0.01 and P = 0.03 at Cycles 1 and 2, respectively). Sarcopenic and cachetic individuals experienced more toxicities and DLT during chemotherapy. The only factors associated with DLT in the multivariate Cox regression analyses including the presence of metastasis and the chemotherapy protocol were cachexia and the ECOG scale (P < 0.001 for both).
Conclusions
Cachexia and ECOG score may identify patients with an increased risk for developing severe toxicity events during chemotherapy treatment for gastrointestinal cancer.

Rocha, I. M. G., Marcadenti, A., Medeiros, G. O. C., Bezerra, R. A., Rego, J. F. M., Gonzalez, M. C., and Fayh, A. P. T. ( 2019) Is cachexia associated with chemotherapy toxicities in gastrointestinal cancer patients? A prospective study. Journal of Cachexia, Sarcopenia and Muscle, 10: 445-454. https://doi.org/10.1002/jcsm.12391.

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     Article first published online:  01 April 2019

Dawit A. Gonçalves, Wilian A. Silveira, Leandro H. Manfredi, Flávia A. Graça, Andrea Armani, Enrico Bertaggia, Brian T. O´Neill, Natalia Lautherbach, Juliano Machado, Leonardo Nogara, Marcelo G. Pereira, Diletta Arcidiacono, Stefano Realdon, C. Ronald Kahn, Marco Sandri, Isis C. Kettelhut, Luiz Carlos C. Navegantes

Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth

Background
Stimulation of β2‐adrenoceptors can promote muscle hypertrophy and fibre type shift, and it can counteract atrophy and weakness. The underlying mechanisms remain elusive.
Methods
Fed wild type (WT), 2‐day fasted WT, muscle‐specific insulin (INS) receptor (IR) knockout (M‐IR−/−), and MKR mice were studied with regard to acute effects of the β2‐agonist formoterol (FOR) on protein metabolism and signalling events. MKR mice express a dominant negative IGF1 receptor, which blocks both INS/IGF1 signalling. All received one injection of FOR (300 μg kg−1 subcutaneously) or saline. Skeletal muscles and serum samples were analysed from 30 to 240 min. For the study of chronic effects of FOR on muscle plasticity and function as well as intracellular signalling pathways, fed WT and MKR mice were treated with formoterol (300 μg kg−1 day−1) for 30 days.
Results
In fed and fasted mice, one injection of FOR inhibited autophagosome formation (LC3‐II content, 65%, P ≤ 0.05) that was paralleled by an increase in serum INS levels (4‐fold to 25‐fold, P ≤ 0.05) and the phosphorylation of Akt (4.4‐fold to 6.5‐fold, P ≤ 0.05) and ERK1/2 (50% to two‐fold, P ≤ 0.05). This led to the suppression (40–70%, P ≤ 0.05) of the master regulators of atrophy, FoxOs, and the mRNA levels of their target genes. FOR enhanced (41%, P ≤ 0.05) protein synthesis only in fed condition and stimulated (4.4‐fold to 35‐fold, P ≤ 0.05) the prosynthetic Akt/mTOR/p70S6K pathway in both fed and fasted states. FOR effects on Akt signalling during fasting were blunted in both M‐IR−/− and MKR mice. Inhibition of proteolysis markers by FOR was prevented only in MKR mice. Blockade of PI3K/Akt axis and mTORC1, but not ERK1/2, in fasted mice also suppressed the acute FOR effects on proteolysis and autophagy. Chronic stimulation of β2‐adrenoceptors in fed WT mice increased body (11%, P ≤ 0.05) and muscle (15%, P ≤ 0.05) growth and downregulated atrophy‐related genes (30–40%, P ≤ 0.05), but these effects were abolished in MKR mice. Increases in muscle force caused by FOR (WT, 24%, P ≤ 0.05) were only partially impaired in MKR mice (12%, P ≤ 0.05), and FOR‐induced slow‐to‐fast fibre type shift was not blocked at all in these animals. In MKR mice, FOR also restored the lower levels of muscle SDH activity to basal WT values and caused a marked reduction (57%, P ≤ 0.05) in the number of centrally nucleated fibers.
Conclusions
NS/IGF1 signalling is necessary for the anti‐proteolytic and hypertrophic effects of in vivo β2‐adrenergic stimulation and appears to mediate FOR‐induced enhancement of protein synthesis. INS/IGF1 signalling only partially contributes to gain in strength and does not mediate fibre type transition induced by FOR.

Gonçalves, D. A., Silveira, W. A., Manfredi, L. H., Graça, F. A., Armani, A., Bertaggia, E., O´Neill, B. T., Lautherbach, N., Machado, J., Nogara, L., Pereira, M. G., Arcidiacono, D., Realdon, S., Kahn, C. R., Sandri, M., Kettelhut, I. C., and Navegantes, L. C. C. ( 2019) Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth. Journal of Cachexia, Sarcopenia and Muscle, 10: 455475. https://doi.org/10.1002/jcsm.12395.

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