Showing papers on "Skeletal muscle published in 2017"

Making muscle: skeletal myogenesis in vivo and in vitro.

Abstract: Skeletal muscle is the largest tissue in the body and loss of its function or its regenerative properties results in debilitating musculoskeletal disorders. Understanding the mechanisms that drive skeletal muscle formation will not only help to unravel the molecular basis of skeletal muscle diseases, but also provide a roadmap for recapitulating skeletal myogenesis in vitro from pluripotent stem cells (PSCs). PSCs have become an important tool for probing developmental questions, while differentiated cell types allow the development of novel therapeutic strategies. In this Review, we provide a comprehensive overview of skeletal myogenesis from the earliest premyogenic progenitor stage to terminally differentiated myofibers, and discuss how this knowledge has been applied to differentiate PSCs into muscle fibers and their progenitors in vitro.

Skeletal muscle inflammation and insulin resistance in obesity

Abstract: Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance.

mTOR as a Key Regulator in Maintaining Skeletal Muscle Mass

Abstract: Maintenance of skeletal muscle mass is regulated by the balance between anabolic and catabolic processes Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase, and is known to play vital roles in protein synthesis Recent findings have continued to refine our understanding of the function of mTOR in maintaining skeletal muscle mass mTOR controls the anabolic and catabolic signaling of skeletal muscle mass, resulting in the modulation of muscle hypertrophy and muscle wastage This review will highlight the fundamental role of mTOR in skeletal muscle growth by summarizing the phenotype of skeletal-specific mTOR deficiency In addition, the evidence that mTOR is a dual regulator of anabolism and catabolism in skeletal muscle mass will be discussed A full understanding of mTOR signaling in the maintenance of skeletal muscle mass could help to develop mTOR-targeted therapeutics to prevent muscle wasting

Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy

Abstract: Mitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3–12 h and mitophagy at 6 h post-exercise in skeletal muscle. These changes were monitored using a novel fluorescent reporter gene, pMitoTimer, that allows assessment of mitochondrial oxidative stress and mitophagy in vivo, and were preceded by increased phosphorylation of AMP activated protein kinase (Ampk) at tyrosine 172 and of unc-51 like autophagy activating kinase 1 (Ulk1) at serine 555. Using mice expressing dominant negative and constitutively active Ampk in skeletal muscle, we demonstrate that Ulk1 activation is dependent on Ampk. Furthermore, exercise-induced metabolic adaptation requires Ulk1. These findings provide direct evidence of exercise-induced mitophagy and demonstrate the importance of Ampk-Ulk1 signaling in skeletal muscle.

Muscle Lipid Metabolism: Role of Lipid Droplets and Perilipins.

Abstract: Skeletal muscle is one of the main regulators of carbohydrate and lipid metabolism in our organism, and therefore, it is highly susceptible to changes in glucose and fatty acid (FA) availability. Skeletal muscle is an extremely complex tissue: its metabolic capacity depends on the type of fibers it is made up of and the level of stimulation it undergoes, such as acute or chronic contraction. Obesity is often associated with increased FA levels, which leads to the accumulation of toxic lipid intermediates, oxidative stress, and autophagy in skeletal fibers. This lipotoxicity is one of the most common causes of insulin resistance (IR). In this scenario, the “isolation” of certain lipids in specific cell compartments, through the action of the specific lipid droplet, perilipin (PLIN) family of proteins, is conceived as a lifeguard compensatory strategy. In this review, we summarize the cellular mechanism underlying lipid mobilization and metabolism inside skeletal muscle, focusing on the function of lipid droplets, the PLIN family of proteins, and how these entities are modified in exercise, obesity, and IR conditions.

Control of muscle formation by the fusogenic micropeptide myomixer

Abstract: Skeletal muscle formation occurs through fusion of myoblasts to form multinucleated myofibers. From a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screen for genes required for myoblast fusion and myogenesis, we discovered an 84–amino acid muscle-specific peptide that we call Myomixer. Myomixer expression coincides with myoblast differentiation and is essential for fusion and skeletal muscle formation during embryogenesis. Myomixer localizes to the plasma membrane, where it promotes myoblast fusion and associates with Myomaker, a fusogenic membrane protein. Myomixer together with Myomaker can also induce fibroblast-fibroblast fusion and fibroblast-myoblast fusion. We conclude that the Myomixer-Myomaker pair controls the critical step in myofiber formation during muscle development.

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

Abstract: Physical exercise can improve brain function and delay neurodegeneration; however, the initial signal from muscle to brain is unknown. Here we show that the lactate receptor (HCAR1) is highly enriched in pial fibroblast-like cells that line the vessels supplying blood to the brain, and in pericyte-like cells along intracerebral microvessels. Activation of HCAR1 enhances cerebral vascular endothelial growth factor A (VEGFA) and cerebral angiogenesis. High-intensity interval exercise (5 days weekly for 7 weeks), as well as L-lactate subcutaneous injection that leads to an increase in blood lactate levels similar to exercise, increases brain VEGFA protein and capillary density in wild-type mice, but not in knockout mice lacking HCAR1. In contrast, skeletal muscle shows no vascular HCAR1 expression and no HCAR1-dependent change in vascularization induced by exercise or lactate. Thus, we demonstrate that a substance released by exercising skeletal muscle induces supportive effects in brain through an identified receptor.

AMPK in skeletal muscle function and metabolism.

Abstract: Skeletal muscle possesses a remarkable ability to adapt to various physiologic conditions. AMPK is a sensor of intracellular energy status that maintains energy stores by fine-tuning anabolic and catabolic pathways. AMPK's role as an energy sensor is particularly critical in tissues displaying highly changeable energy turnover. Due to the drastic changes in energy demand that occur between the resting and exercising state, skeletal muscle is one such tissue. Here, we review the complex regulation of AMPK in skeletal muscle and its consequences on metabolism ( e.g., substrate uptake, oxidation, and storage as well as mitochondrial function of skeletal muscle fibers). We focus on the role of AMPK in skeletal muscle during exercise and in exercise recovery. We also address adaptations to exercise training, including skeletal muscle plasticity, highlighting novel concepts and future perspectives that need to be investigated. Furthermore, we discuss the possible role of AMPK as a therapeutic target as well as different AMPK activators and their potential for future drug development.-Kjobsted, R., Hingst, J. R., Fentz, J., Foretz, M., Sanz, M.-N., Pehmoller, C., Shum, M., Marette, A., Mounier, R., Treebak, J. T., Wojtaszewski, J. F. P., Viollet, B., Lantier, L. AMPK in skeletal muscle function and metabolism.

Skeletal Muscle Remodeling in Response to Eccentric vs. Concentric Loading: Morphological, Molecular, and Metabolic Adaptations

Abstract: Skeletal muscle contracts either by shortening or lengthening (concentrically or eccentrically, respectively); however, the two contractions substantially differ from one another in terms of mechanisms of force generation, maximum force production and energy cost. It is generally known that eccentric actions generate greater force than isometric and concentric contractions and at a lower metabolic cost. Hence, by virtue of the greater mechanical loading involved in active lengthening, eccentric resistance training (ECC RT) is assumed to produce greater hypertrophy than concentric resistance training (CON RT). Nonetheless, prevalence of either ECC RT or CON RT in inducing gains in muscle mass is still an open issue, with some studies reporting greater hypertrophy with eccentric, some with concentric and some with similar hypertrophy within both training modes. Recent observations suggest that such hypertrophic responses to lengthening vs. shortening contractions are achieved by different adaptations in muscle architecture. Whilst the changes in muscle protein synthesis in response to acute and chronic concentric and eccentric exercise bouts seem very similar, the molecular mechanisms regulating the myogenic adaptations to the two distinct loading stimuli are still incompletely understood. Thus, the present review aims to, (a) critically discuss the literature on the contribution of eccentric vs. concentric loading to muscular hypertrophy and structural remodeling, and, (b) clarify the molecular mechanisms that may regulate such adaptations. We conclude that, when matched for either maximum load or work, similar increase in muscle size is found between ECC and CON RT. However, such hypertrophic changes appear to be achieved through distinct structural adaptations, which may be regulated by different myogenic and molecular responses observed between lengthening and shortening contractions.

Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice

Abstract: We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Here we report that treatment with recombinant Irisin prevented bone loss in hind-limb suspended mice when administered during suspension (preventive protocol) and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks (curative protocol). MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented a dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin protected against muscle mass decline in the hind-limb suspended mice, and maintained the fiber cross-sectional area. Notably, the decrease of myosin type II expression in unloaded mice was completely prevented by r-Irisin administration. Our data reveal for the first time that Irisin retrieves disuse‐induced bone loss and muscle atrophy. These findings may lead to development of an Irisin-based therapy for elderly immobile osteoporotic and physically disable patients, and might represent a countermeasure for astronauts subjected to microgravity-induced bone and muscle losses.

Skeletal Muscle as an Endocrine Organ: The Role of Myokines in Exercise Adaptations

Abstract: Exercise stimulates the release of proteins with autocrine, paracrine, or endocrine functions produced in skeletal muscle, termed myokines. Based on the current state of knowledge, the major physiological function of myokines is to protect the functionality and to enhance the exercise capacity of skeletal muscle. Myokines control adaptive processes in skeletal muscle by acting as paracrine regulators of fuel oxidation, hypertrophy, angiogenesis, inflammatory processes, and regulation of the extracellular matrix. Endocrine functions attributed to myokines are involved in body weight regulation, low-grade inflammation, insulin sensitivity, suppression of tumor growth, and improvement of cognitive function. Muscle-derived regulatory RNAs and metabolites, as well as the design of modified myokines, are promising novel directions for treatment of chronic diseases.

Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss.

Abstract: Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. Here we show that bioconstructs suffused with genetically-labelled muscle stem cells (MuSCs) and other muscle resident cells (MRCs) are effective to treat VML injuries in mice. Imaging of bioconstructs implanted in damaged muscles indicates MuSCs survival and growth, and ex vivo analyses show force restoration of treated muscles. Histological analysis highlights myofibre formation, neovascularisation, but insufficient innervation. Both innervation and in vivo force production are enhanced when implantation of bioconstructs is followed by an exercise regimen. Significant improvements are also observed when bioconstructs are used to treat chronic VML injury models. Finally, we demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML.

Mechanisms and mediators of the skeletal muscle repeated bout effect

Abstract: Skeletal muscle adapts to exercise-induced damage by orchestrating several but still poorly understood mechanisms that endow protection from subsequent damage Known widely as the repeated bout effect, we propose that neural adaptations, alterations to muscle mechanical properties, structural remodeling of the extracellular matrix, and biochemical signaling work in concert to coordinate the protective adaptation

Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy

Abstract: Exercise induces expression of the myokine irisin, which is known to promote browning of white adipose tissue and has been shown to mediate beneficial effects following exercise. Here we show that irisin induces expression of a number of pro-myogenic and exercise response genes in myotubes. Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling. Injection of irisin in mice induces significant hypertrophy and enhances grip strength of uninjured muscle. Following skeletal muscle injury, irisin injection improves regeneration and induces hypertrophy. The effects of irisin on hypertrophy are due to activation of satellite cells and enhanced protein synthesis. In addition, irisin injection rescues loss of skeletal muscle mass following denervation by enhancing satellite cell activation and reducing protein degradation. These data suggest that irisin functions as a pro-myogenic factor in mice.

Myomerger induces fusion of non-fusogenic cells and is required for skeletal muscle development.

Abstract: Despite the importance of cell fusion for mammalian development and physiology, the factors critical for this process remain to be fully defined, which has severely limited our ability to reconstitute cell fusion Myomaker (Tmem8c) is a muscle-specific protein required for myoblast fusion Expression of myomaker in fibroblasts drives their fusion with myoblasts, but not with other myomaker-expressing fibroblasts, highlighting the requirement of additional myoblast-derived factors for fusion Here we show that Gm7325, which we name myomerger, induces the fusion of myomaker-expressing fibroblasts Thus, myomaker and myomerger together confer fusogenic activity to otherwise non-fusogenic cells Myomerger is skeletal muscle-specific and genetic deletion in mice results in a paucity of muscle fibres demonstrating its requirement for normal muscle formation Myomerger deficient myocytes differentiate and harbour organized sarcomeres but are fusion-incompetent Our findings identify myomerger as a fundamental myoblast fusion protein and establish a system that begins to reconstitute mammalian cell fusion

Overview of the Muscle Cytoskeleton.

Abstract: Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. © 2017 American Physiological Society. Compr Physiol 7:891-944, 2017.

The structural basis of ryanodine receptor ion channel function

Abstract: Large-conductance Ca2+ release channels known as ryanodine receptors (RyRs) mediate the release of Ca2+ from an intracellular membrane compartment, the endo/sarcoplasmic reticulum. There are three mammalian RyR isoforms: RyR1 is present in skeletal muscle; RyR2 is in heart muscle; and RyR3 is expressed at low levels in many tissues including brain, smooth muscle, and slow-twitch skeletal muscle. RyRs form large protein complexes comprising four 560-kD RyR subunits, four ∼12-kD FK506-binding proteins, and various accessory proteins including calmodulin, protein kinases, and protein phosphatases. RyRs share ∼70% sequence identity, with the greatest sequence similarity in the C-terminal region that forms the transmembrane, ion-conducting domain comprising ∼500 amino acids. The remaining ∼4,500 amino acids form the large regulatory cytoplasmic "foot" structure. Experimental evidence for Ca2+, ATP, phosphorylation, and redox-sensitive sites in the cytoplasmic structure have been described. Exogenous effectors include the two Ca2+ releasing agents caffeine and ryanodine. Recent work describing the near atomic structures of mammalian skeletal and cardiac muscle RyRs provides a structural basis for the regulation of the RyRs by their multiple effectors.

Low skeletal muscle radiation attenuation and visceral adiposity are associated with overall survival and surgical site infections in patients with pancreatic cancer.

Abstract: Background Cancer cachexia and skeletal muscle wasting are related to poor survival. In this study, quantitative body composition measurements using computed tomography (CT) were investigated in relation to survival, post-operative complications, and surgical site infections in surgical patients with cancer of the head of the pancreas. Methods A prospective cohort of 199 patients with cancer of the head of the pancreas was analysed by CT imaging at the L3 level to determine (i) muscle radiation attenuation (average Hounsfield units of total L3 skeletal muscle); (ii) visceral adipose tissue area; (iii) subcutaneous adipose tissue area; (iv) intermuscular adipose tissue area; and (v) skeletal muscle area. Sex-specific cut-offs were determined at the lower tertile for muscle radiation attenuation and skeletal muscle area and the higher tertile for adipose tissues. These variables of body composition were related to overall survival, severe post-operative complications (Dindo–Clavien ≥ 3), and surgical site infections (wounds inspected daily by an independent trial nurse) using Cox-regression analysis and multivariable logistic regression analysis, respectively. Results Low muscle radiation attenuation was associated with shorter survival in comparison with moderate and high muscle radiation attenuation [median survival 10.8 (95% CI: 8.8–12.8) vs. 17.4 (95% CI: 14.7–20.1), and 18.5 (95% CI: 9.2–27.8) months, respectively; P < 0.008]. Patient subgroups with high muscle radiation attenuation combined with either low visceral adipose tissue or age <70 years had longer survival than other subgroups (P = 0.011 and P = 0.001, respectively). Muscle radiation attenuation was inversely correlated with intermuscular adipose tissue (rp = −0.697, P < 0.001). High visceral adipose tissue was associated with an increased surgical site infection rate, OR: 2.4 (95% CI: 1.1–5.3; P = 0.027). Conclusions Low muscle radiation attenuation was associated with reduced survival, and high visceral adiposity was associated with an increase in surgical site infections. The strong correlation between muscle radiation attenuation and intermuscular adipose tissue suggests the presence of ectopic fat in muscle, warranting further investigation. CT image analysis could be implemented in pre-operative risk assessment to assist in treatment decision-making.