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Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin–proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo . Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.

FGF19 acts directly on skeletal muscle to increase its mass, and treatment with the hormone ameliorates muscle atrophy in three mouse models. The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease 1 . Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro . These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo , FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of β-Klotho ( KLB ), an obligate co-receptor for FGF15/19 (refs. 2 , 3 ), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting.

High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H(2)O(2) emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H(2)O(2) emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

Muscle loss due to fibrotic or adipogenic replacement of myofibers is common in muscle diseases and muscle-resident fibro/adipogenic precursors (FAPs) are implicated in this process. While FAP-mediated muscle fibrosis is widely studied in muscle diseases, the role of FAPs in adipogenic muscle loss is not well understood. Adipogenic muscle loss is a feature of limb girdle muscular dystrophy 2B (LGMD2B) – a disease caused by mutations in dysferlin. Here we show that FAPs cause the adipogenic loss of dysferlin deficient muscle. Progressive accumulation of Annexin A2 (AnxA2) in the myofiber matrix causes FAP differentiation into adipocytes. Lack of AnxA2 prevents FAP adipogenesis, protecting against adipogenic loss of dysferlinopathic muscle while exogenous AnxA2 enhances muscle loss. Pharmacological inhibition of FAP adipogenesis arrests adipogenic replacement and degeneration of dysferlin-deficient muscle. These results demonstrate the pathogenic role of FAPs in LGMD2B and establish these cells as therapeutic targets to ameliorate muscle loss in patients. Fibroadipogenic precursor cells (FAPs) contribute to fibrosis and adipogenic replacement in muscular dystrophies. Here, the authors show that FAPs contribute to adipogenic loss in mouse models of limb girdle muscular dystrophy 2B via a mechanism dependent on expression of Annexin A2, and that this process can be prevented by its pharmacologic inhibition in mice.

Muscle cell death in polymyositis is induced by CD8 + cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8 + cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8 + cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes. Polymyositis (PM) is a chronic inflammatory myopathy characterized by progressive muscle weakness. Here the authors showed that muscle fibers in PM undergo necroptosis and aggravate inflammation via releasing pro-inflammatory molecules such as HMGB1.

The muscoskeletal system can be irradiated with wavelengths in the red and near infrared regions which penetrate deep into the body and stimulate biological mechanisms. However, the activation of cellular responses in muscle, specifically actively contracting, is not clearly understood. Therefore, we investigated biological effects induced by irradiation with 810 nm wavelength of light in myotubes, resting or actively contracting in an acute model of exercise. In resting myotubes, cytosolic Ca 2+ rose within 10 minutes post treatment with 810 nm at 2–4 J/cm 2 . ATP production was increased 4% ± 3 at 24 hrs post light treatment. In contracting myotubes, 810 nm treatment resulted in a significant ~30% increase in intracellular ATP levels and a 20% ± 12 reduction in lactate secretion into cell culture media. 810 nm treated myotubes also had a smaller change in myotube width during contractions, 5% ± 3, suggesting the myotubes were contracting with less force. Although the contractile motion was reduced, 810 nm treated myotubes had a higher frequency of spontaneous contractions after removal of electric pulse stimulation (EPS), 42% ± 21 and 1.3-2 – fold increase in mitochondrial proteins, Tom70, citrate synthase (CS) and succinate dehydrogenase (SDHA). This finding suggests that 810 nm treatment altered metabolic and contractile properties of myotubes due to mitochondrial activation. A more thorough understanding of these effects could lead to new treatment modalities that could improve physical performance.

Adult skeletal muscle is capable of complete regeneration after an acute injury. The main parameter studied to assess muscle regeneration efficacy is the cross-sectional area (CSA) of the myofibers as myofiber size correlates with muscle force. CSA analysis can be time-consuming and may trigger variability in the results when performed manually. This is why programs were developed to completely automate the analysis of the CSA, such as SMASH, MyoVision, or MuscleJ softwares. Although these softwares are efficient to measure CSA on normal or hypertrophic/atrophic muscle, they fail to efficiently measure CSA on regenerating muscles. We developed Open-CSAM, an ImageJ macro, to perform a high throughput semi-automated analysis of CSA on skeletal muscle from various experimental conditions. The macro allows the experimenter to adjust the analysis and correct the mistakes done by the automation, which is not possible with fully automated programs. We showed that Open-CSAM was more accurate to measure CSA in regenerating and dystrophic muscles as compared with SMASH, MyoVision, and MuscleJ softwares and that the inter-experimenter variability was negligible. We also showed that, to obtain a representative CSA measurement, it was necessary to analyze the whole muscle section and not randomly selected pictures, a process that was easily and accurately be performed using Open-CSAM. To conclude, we show here an easy and experimenter-controlled tool to measure CSA in muscles from any experimental condition, including regenerating muscle.

Background Vitamin D contributes to the optimal functioning of muscles. This study was designed to determine the modulating effect of vitamin D supplementation on the degree of muscle cell damage caused by eccentric exercise in young men. Methods 60 male volunteers (20–24 years old) taking part in this study were divided in two groups - with suboptimal (S) and optimal (O;) 25(OH)D plasma levels. These groups were randomly subdivided into groups with vitamin D supplementation (experimental: SE and OE) and controls (SC and OC). Before the supplementation (Test I) and after 3 months (Test II), participants were subjected to two rounds of eccentric exercise tests on a declined treadmill (running speed corresponded 60% VO2peak determined in each subject in incremental exercise test). During each test, blood samples used for determination of 25(OH)D, Il-1β, myoglobin (Mb) levels and CK, LDH activity were taken at three timepoints: before the test, 1 h and 24 h after it ended. After distribution normality testing (Saphiro-Wilk test), statistical analyses were performed. Non-parametric: Kruskal-Wallis test and the Wilcoxon test were applied, and the Dunn-Bonferroni test as a post-hoc test. Results In all groups, after 3 months, higher concentrations of 25(OH)D were indicated (SE p  = 0.005; SC p  = 0.018; OE p =  0.018; OC p  = 0.028). SE and SC groups showed higher baseline concentrations of Il-1β and significantly higher concentrations of this interleukin after 1 h compared to groups with an optimal 25(OH)D level. After supplementation, the SE group reacted with a similar jump in concentration of Il-1β as the OC and OE groups. The change after 1 h after exercise in Test II was significantly different from that from Test I ( p  = 0.047) in SE group. Lower Mb concentrations indicated 1 h after exercise in Test II for SC and SE groups were indicated. CK activity did not differentiate the studied groups. Plasma calcium and phosphate disorders were also not indicated. Conclusions The study has shown that vitamin D doses determined from the plasma concentration of 25(OH)D of individuals to match their specific needs can significantly reduce muscle cell damage induced by eccentric exercise.

The apoptotic event of phosphatidylserine exposure and its recognition by the receptor BAI1 has an unexpected new role as a signal enhancing mouse myoblast fusion, an insight with relevance to some congenital muscle diseases and muscle injury treatments. A signalling function for dead cells Apoptotic cell death occurs throughout development and homeostasis in healthy tissues, including skeletal muscle. This study questions previous assumptions that the resulting dead cells have no beneficial effects. Kodi Ravichandran and colleagues show that during skeletal muscle differentiation in mice, a fraction of precursor muscle cells undergoes apoptosis, and that these cells provide a key signal — phosphatidylserine — that promotes muscle development. The idea that the body may use cell death not only to rid itself of unwanted cells, but also to regulate differentiation adds an intriguing dimension to cell turnover within tissues. Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibres 1 , 2 . Although conserved transcription factors and signalling proteins involved in myogenesis have been identified, upstream regulators are less well understood. Here we report an unexpected discovery that the membrane protein BAI1, previously linked to recognition of apoptotic cells by phagocytes 3 , promotes myoblast fusion. Endogenous BAI1 expression increased during myoblast fusion, and BAI1 overexpression enhanced myoblast fusion by means of signalling through ELMO/Dock180/Rac1 proteins 4 . During myoblast fusion, a fraction of myoblasts within the population underwent apoptosis and exposed phosphatidylserine, an established ligand for BAI1 (ref. 3 ). Blocking apoptosis potently impaired myoblast fusion, and adding back apoptotic myoblasts restored fusion. Furthermore, primary human myoblasts could be induced to form myotubes by adding apoptotic myoblasts, even under normal growth conditions. Mechanistically, apoptotic cells did not directly fuse with the healthy myoblasts, rather the apoptotic cells induced a contact-dependent signalling with neighbours to promote fusion among the healthy myoblasts. In vivo , myofibres from Bai1 −/− mice are smaller than those from wild-type littermates. Muscle regeneration after injury was also impaired in Bai1 −/− mice, highlighting a role for BAI1 in mammalian myogenesis. Collectively, these data identify apoptotic cells as a new type of cue that induces signalling via the phosphatidylserine receptor BAI1 to promote fusion of healthy myoblasts, with important implications for muscle development and repair.

Cachexia-inducing tumors release complex factors that promote the increased uptake and burning of fats by muscle, resulting in muscle atrophy—a process that can be blocked if fatty acid oxidation is pharmacologically inhibited. Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer 1 , 2 , presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer 3 , 4 , 5 . Additionally, although many people with cachexia show hypermetabolism 3 , 6 , the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell–based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo . Therefore, fatty acid–induced oxidative stress could be targeted to prevent cancer-induced cachexia.