Showing papers on "Skeletal muscle published in 2022"

Skeletal muscle alterations in patients with acute Covid‐19 and post‐acute sequelae of Covid‐19

Abstract: Skeletal muscle‐related symptoms are common in both acute coronavirus disease (Covid)‐19 and post‐acute sequelae of Covid‐19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post‐viral fatigue syndrome. Patients with severe Covid‐19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid‐19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post‐intensive care unit (ICU) syndrome and ICU‐acquired weakness and likely explain a substantial part of Covid‐19‐acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS‐CoV)‐2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS‐CoV‐2‐specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid‐19 and PASC.

Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults

Abstract: This randomized clinical trial evaluates the improvement in the 6-minute walk distance test and in leg and hand muscle endurance after use of urolithin A in patients aged 65 to 90 years.

Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults

Abstract: Targeting mitophagy to activate the recycling of faulty mitochondria during aging is a strategy to mitigate muscle decline. We present results from a randomized, placebo-controlled trial in middle-aged adults where we administer a postbiotic compound Urolithin A (Mitopure), a known mitophagy activator, at two doses for 4 months (NCT03464500). The data show significant improvements in muscle strength (∼12%) with intake of Urolithin A. We observe clinically meaningful improvements with Urolithin A on aerobic endurance (peak oxygen oxygen consumption [VO2]) and physical performance (6 min walk test) but do not notice a significant improvement on peak power output (primary endpoint). Levels of plasma acylcarnitines and C-reactive proteins are significantly lower with Urolithin A, indicating higher mitochondrial efficiency and reduced inflammation. We also examine expression of proteins linked to mitophagy and mitochondrial metabolism in skeletal muscle and find a significant increase with Urolithin A administration. This study highlights the benefit of Urolithin A to improve muscle performance.

Hydrogel-Based Fiber Biofabrication Techniques for Skeletal Muscle Tissue Engineering

Abstract: The functional capabilities of skeletal muscle are strongly correlated with its well-arranged microstructure, consisting of parallelly aligned myotubes. In case of extensive muscle loss, the endogenous regenerative capacity is hindered by scar tissue formation, which compromises the native muscle structure, ultimately leading to severe functional impairment. To address such an issue, skeletal muscle tissue engineering (SMTE) attempts to fabricate in vitro bioartificial muscle tissue constructs to assist and accelerate the regeneration process. Due to its dynamic nature, SMTE strategies must employ suitable biomaterials (combined with muscle progenitors) and proper 3D architectures. In light of this, 3D fiber-based strategies are gaining increasing interest for the generation of hydrogel microfibers as advanced skeletal muscle constructs. Indeed, hydrogels possess exceptional biomimetic properties, while the fiber-shaped morphology allows for the creation of geometrical cues to guarantee proper myoblast alignment. In this review, we summarize commonly used hydrogels in SMTE and their main properties, and we discuss the first efforts to engineer hydrogels to guide myoblast anisotropic orientation. Then, we focus on presenting the main hydrogel fiber-based techniques for SMTE, including molding, electrospinning, 3D bioprinting, extrusion, and microfluidic spinning. Furthermore, we describe the effect of external stimulation (i.e., mechanical and electrical) on such constructs and the application of hydrogel fiber-based methods on recapitulating complex skeletal muscle tissue interfaces. Finally, we discuss the future developments in the application of hydrogel microfibers for SMTE.

Selenoprotein K protects skeletal muscle from damage and is required for satellite cells-mediated myogenic differentiation

Abstract: The regeneration of adult skeletal muscle after injury is primarily initiated by satellite cells (SCs), but the regulatory mechanisms of cells committed to myogenic differentiation remain poorly explored. Small molecular selenoprotein K (SelK) plays crucial roles in the modulation of endoplasmic reticulum (ER) stress and against oxidative stress. Here, we first showed that SelK expression is activated in myogenic cells during differentiation both in vivo and in vitro. Meanwhile, loss of SelK delayed skeletal muscle regeneration, inhibited the development of myoblasts into myotubes, and was accompanied by reduced expression of myogenic regulatory factors (MRFs). Moreover, ER stress, intracellular reactive oxygen species (ROS), autophagy and apoptosis under myogenesis induction were more severe in SelK-deficient mice and cells than in the corresponding control groups. Supplementation with specific inhibitors to alleviate excessive ER stress or oxidative stress partly rescued the differentiation potential and formation of myotubes. Notably, we demonstrated that Self-mediated regulation of cellular redox status was primarily derived from its subsequent effects on ER stress. Together, our results suggest that SelK protects skeletal muscle from damage and is a crucial regulator of myogenesis.

Bioinks and Bioprinting Strategies for Skeletal Muscle Tissue Engineering

Abstract: Skeletal muscles play important roles in critical body functions and their injury or disease can lead to limitation of mobility and loss of independence. Current treatments result in variable functional recovery, while reconstructive surgery, as the gold-standard approach, is limited due to donor shortage, donor-site morbidity, and limited functional recovery. Skeletal muscle tissue engineering (SMTE) has generated enthusiasm as an alternative solution for treatment of injured tissue and serves as a functional disease model. Recently, bioprinting has emerged as a promising tool for recapitulating the complex and highly organized architecture of skeletal muscles at clinically relevant sizes. Here, skeletal muscle physiology, muscle regeneration following injury, and current treatments following muscle loss are discussed, and then bioprinting strategies implemented for SMTE are critically reviewed. Subsequently, recent advancements that have led to improvement of bioprinting strategies to construct large muscle structures, boost myogenesis in vitro and in vivo, and enhance tissue integration are discussed. Bioinks for muscle bioprinting, as an essential part of any bioprinting strategy, are discussed, and their benefits, limitations, and areas to be improved are highlighted. Finally, the directions the field should expand to make bioprinting strategies more translational and overcome the clinical unmet needs are discussed.

Characterization of cellular senescence in aging skeletal muscle

Abstract: Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single cell and bulk RNA-sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16Ink4a together with multiple senescence-related genes and, concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p2Cip1 . Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.

Gut microbes and muscle function: can probiotics make our muscles stronger?

Abstract: Evidence suggests that gut microbiota composition and diversity can be a determinant of skeletal muscle metabolism and functionality. This is true in catabolic (sarcopenia and cachexia) or anabolic (exercise or in athletes) situations. As gut microbiota is known to be causal in the development and worsening of metabolic dysregulation phenotypes such as obesity or insulin resistance, it can regulate, at least partially, skeletal muscle mass and function. Skeletal muscles are physiologically far from the gut. Signals generated by the gut due to its interaction with the gut microbiome (microbial metabolites, gut peptides, lipopolysaccharides, and interleukins) constitute links between gut microbiota activity and skeletal muscle and regulate muscle functionality via modulation of systemic/tissue inflammation as well as insulin sensitivity. The probiotics able to limit sarcopenia and cachexia or promote health performances in rodents are mainly lactic acid bacteria and bifidobacteria. In humans, the same bacteria have been tested, but the scarcity of the studies, the variability of the populations, and the difficulty to measure accurately and with high reproducibility muscle mass and function have not allowed to highlight specific strains able to optimize muscle mass and function. Further studies are required on more defined population, in order to design personalized nutrition. For elderly, testing the efficiency of probiotics according to the degree of frailty, nutritional state, or degree of sarcopenia before supplementation is essential. For exercise, selection of probiotics capable to be efficient in recreational and/or elite athletes, resistance, and/or endurance exercise would also require further attention. Ultimately, a combination of strategies capable to optimize muscle functionality, including bacteria (new microbes, bacterial ecosystems, or mix, more prone to colonize a specific gut ecosystem) associated with prebiotics and other ‘traditional’ supplements known to stimulate muscle anabolism (e.g. proteins), could be the best way to preserve muscle functionality in healthy individuals at all ages or patients.

Healthy aging and muscle function are positively associated with NAD+ abundance in humans

Abstract: Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD+) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD+ levels that were more similar to those found in younger individuals. NAD+ abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD+ and health status in human aging.

Sarcopenia in Patients with Cirrhosis after Transjugular Intrahepatic Portosystemic Shunt Placement.

Abstract: Background Sarcopenia is frequently found in patients with cirrhosis and is associated with liver dysfunction, cirrhosis-related complications, and poorer quality of life. Purpose To evaluate changes in skeletal muscle and fat mass at CT and to evaluate the relationship of sarcopenia to mortality in patients with cirrhosis after transjugular intrahepatic portosystemic shunt (TIPS) placement. Materials and Methods Patients who underwent TIPS between August 2016 and May 2020 were included in this retrospective study. Skeletal muscle and fat mass were evaluated at CT at the L3 vertebra at baseline and at 2 months, 5 months, and 1 year after TIPS. Sarcopenia was defined as L3 skeletal muscle index (SMI) less than 50 cm2/m2 for men and less than 39 cm2/m2 for women. The primary end point was change in skeletal muscle and fat mass, and secondary end points included survival and the predictive factors for survival. Changes in skeletal muscle and fat mass over time were analyzed by generalized estimating equations. Results A total of 224 patients (159 men [113 with and 46 without sarcopenia] and 65 women [32 with and 33 without sarcopenia]) were included. In male patients with sarcopenia, the mean L3 SMI increased from 41.8 cm2/m2 (baseline) to 49.1 cm2/m2 (at 5-month follow-up; P < .001) and 49.6 cm2/m2 (at 1-year follow-up; P < .001) after TIPS. In female patients with sarcopenia, SMI increased from 33.7 cm2/m2 (at baseline) to 40.6 cm2/m2 (at 5-month follow-up; P < .001) and 42.0 cm2/m2 (at 1-year follow-up; P < .001) after TIPS. Sarcopenia (hazard ratio, 3.0; 95% CI: 1.2, 7.8) was identified as an independent risk factor for mortality after TIPS, and the patients who converted from sarcopenic to nonsarcopenic had higher cumulative survival rate than those who did not (96.4% vs 82.1%; log-rank P = .04). Conclusion In patients with sarcopenia, both skeletal muscle and fat mass increased after transjugular intrahepatic portosystemic shunt placement. The reversal of sarcopenia could reduce the risk of death. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee in this issue.

A Review of Sarcopenia Pathophysiology, Diagnosis, Treatment and Future Direction

Abstract: Sarcopenia is a progressive and generalized loss of skeletal muscle mass and function. The prevalence of sarcopenia was reported to be up to 29% in older persons in the community healthcare setting. Sarcopenia diagnosis is confirmed by the presence of low muscle mass plus low muscle strength or low physical performance. Sarcopenia management options include non-pharmacological and pharmacological approaches. Non-pharmacological approaches include resistance exercise and adequate nutrition. Of the two, resistance exercise is the standard non-pharmacological treatment approach for sarcopenia with significant positive evidence. Some dietary approaches such as adequate intake of protein, vitamin D, antioxidant nutrients, and long-chain polyunsaturated fatty acid have been shown to have positive effects against sarcopenia. Currently, no specific drugs have been approved by the Food and Drug Administration for the treatment of sarcopenia. However, several agents, including growth hormone, anabolic or androgenic steroids, selective androgenic receptor modulators, protein anabolic agents, appetite stimulants, myostatin inhibitors, activating II receptor drugs, β-receptor blockers, angiotensin-converting enzyme inhibitors, and troponin activators, are recommended and have been shown to have variable efficacy. Future research should focus on sarcopenia biological pathway and improved diagnostic approaches such as biomarkers for early detection, development of consistently pre-eminent treatment methods for severe sarcopenia patients, and establishing sensitive measures for predicting sarcopenia treatment response.

Extracellular vesicle secretion is tissue-dependent ex vivo and skeletal muscle myofiber extracellular vesicles reach the circulation in vivo

Abstract: Extracellular vesicles (EVs) are biomarkers and modifiers of human disease. EVs secreted by insulin-responsive tissues like skeletal muscle (SkM) and white adipose tissue (WAT) contribute to metabolic health and disease but the relative abundance of EVs from these tissues has not been directly examined. Human Protein Atlas data and directly measuring EV secretion in mouse SkM and WAT using an ex vivo tissue explant model confirmed that SkM tissue secretes more EVs than WAT. Differences in EV secretion between SkM and WAT were not due to SkM contraction but may be explained by differences in tissue metabolic capacity. We next examined how many EVs secreted from SkM tissue ex vivo and in vivo are myofiber-derived. To do this, a SkM myofiber-specific dual fluorescent reporter mouse was created. Spectral flow cytometry revealed that SkM myofibers are a major source of SkM tissue-derived EVs ex vivo and EV immunocapture indicates that ∼5% of circulating tetraspanin-positive EVs are derived from SkM myofibers in vivo. Our findings demonstrate that 1) SkM secretes more EVs than WAT, 2) many SkM tissue EVs are derived from SkM myofibers, and 3) SkM myofiber-derived EVs reach the circulation in vivo. These findings advance our understanding of EV secretion between metabolically active tissues and provide direct evidence that SkM myofibers secrete EVs that can reach the circulation in vivo.

Skeletal muscle derived Musclin protects the heart during pathological overload

Abstract: Abstract Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn , which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Exercise-mediated reinnervation of skeletal muscle in elderly people: An update

Abstract: Sarcopenia is defined by the loss of muscle mass and function. In aging sarcopenia is due to mild chronic inflammation but also to fiber-intrinsic defects, such as mitochondrial dysfunction. Age-related sarcopenia is associated with physical disability and lowered quality of life. In addition to skeletal muscle, the nervous tissue is also affected in elderly people. With aging, type 2 fast fibers preferentially undergo denervation and are reinnervated by slow-twitch motor neurons. They spread forming new neuro-muscular junctions with the denervated fibers: the result is an increased proportion of slow fibers that group together since they are associated in the same motor unit. Grouping and fiber type shifting are indeed major histological features of aging skeletal muscle. Exercise has been proposed as an intervention for age-related sarcopenia due to its numerous beneficial effects on muscle mechanical and biochemical features. In 2013, a precursor study in humans was published in the European Journal of Translation Myology (formerly known as Basic and Applied Myology), highlighting the occurrence of reinnervation in the musculature of aged, exercise-trained individuals as compared to the matching control. This paper, entitled «Reinnervation of Vastus lateralis is increased significantly in seniors (70-years old) with a lifelong history of high-level exercise», is now being reprinted for the second issue of the «Ejtm Seminal Paper Series». In this short review we discuss those results in the light of the most recent advances confirming the occurrence of exercise-mediated reinnervation, ultimately preserving muscle structure and function in elderly people who exercise.

Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging

Abstract: Functional status is considered the main determinant of healthy aging. Impairment in skeletal muscle and the cardiovascular system, two interrelated systems, results in compromised functional status in aging. Increased oxidative stress and inflammation in older subjects constitute the background for skeletal muscle and cardiovascular system alterations. Aged skeletal muscle mass and strength impairment is related to anabolic resistance, mitochondrial dysfunction, increased oxidative stress and inflammation as well as a reduced antioxidant response and myokine profile. Arterial stiffness and endothelial function stand out as the main cardiovascular alterations related to aging, where increased systemic and vascular oxidative stress and inflammation play a key role. Physical activity and exercise training arise as modifiable determinants of functional outcomes in older persons. Exercise enhances antioxidant response, decreases age-related oxidative stress and pro-inflammatory signals, and promotes the activation of anabolic and mitochondrial biogenesis pathways in skeletal muscle. Additionally, exercise improves endothelial function and arterial stiffness by reducing inflammatory and oxidative damage signaling in vascular tissue together with an increase in antioxidant enzymes and nitric oxide availability, globally promoting functional performance and healthy aging. This review focuses on the role of oxidative stress and inflammation in aged musculoskeletal and vascular systems and how physical activity/exercise influences functional status in the elderly.

Guidance for assessment of the muscle mass phenotypic criterion for the Global Leadership Initiative on Malnutrition diagnosis of malnutrition.

Abstract: The Global Leadership Initiative on Malnutrition (GLIM) provides consensus criteria for the diagnosis of malnutrition that can be widely applied. The GLIM approach is based on the assessment of three phenotypic (weight loss, low body mass index, and low skeletal muscle mass) and two etiologic (low food intake and presence of disease with systemic inflammation) criteria, with diagnosis confirmed by any combination of one phenotypic and one etiologic criterion fulfilled. Assessment of muscle mass is less commonly performed than other phenotypic malnutrition criteria, and its interpretation may be less straightforward, particularly in settings that lack access to skilled clinical nutrition practitioners and/or to body composition methodologies. In order to promote the widespread assessment of skeletal muscle mass as an integral part of the GLIM diagnosis of malnutrition, the GLIM consortium appointed a working group to provide consensus-based guidance on assessment of skeletal muscle mass. When such methods and skills are available, quantitative assessment of muscle mass should be measured or estimated using dual-energy x-ray absorptiometry, computerized tomography, or bioelectrical impedance analysis. For settings where these resources are not available, then the use of anthropometric measures and physical examination are also endorsed. Validated ethnic- and sex-specific cutoff values for each measurement and tool are recommended when available. Measurement of skeletal muscle function is not advised as surrogate measurement of muscle mass. However, once malnutrition is diagnosed, skeletal muscle function should be investigated as a relevant component of sarcopenia and for complete nutrition assessment of persons with malnutrition.

Senolytic treatment rescues blunted muscle hypertrophy in old mice

Abstract: With aging, skeletal muscle plasticity is attenuated in response to exercise. Here, we report that senescent cells, identified using senescence-associated β-galactosidase (SA β-Gal) activity and p21 immunohistochemistry, are very infrequent in resting muscle, but emerge approximately 2 weeks after a bout of resistance exercise in humans. We hypothesized that these cells contribute to blunted hypertrophic potential in old age. Using synergist ablation-induced mechanical overload (MOV) of the plantaris muscle to model resistance training in adult (5-6-month) and old (23-24-month) male C57BL/6 J mice, we found increased senescent cells in both age groups during hypertrophy. Consistent with the human data, there were negligible senescent cells in plantaris muscle from adult and old sham controls, but old mice had significantly more senescent cells 7 and 14 days following MOV relative to young. Old mice had blunted whole-muscle hypertrophy when compared to adult mice, along with smaller muscle fibers, specifically glycolytic type 2x + 2b fibers. To ablate senescent cells using a hit-and-run approach, old mice were treated with vehicle or a senolytic cocktail consisting of 5 mg/kg dasatinib and 50 mg/kg quercetin (D + Q) on days 7 and 10 during 14 days of MOV; control mice underwent sham surgery with or without senolytic treatment. Old mice given D + Q had larger muscles and muscle fibers after 14 days of MOV, fewer senescent cells when compared to vehicle-treated old mice, and changes in the expression of genes (i.e., Igf1, Ddit4, Mmp14) that are associated with hypertrophic growth. Our data collectively show that senescent cells emerge in human and mouse skeletal muscle following a hypertrophic stimulus and that D + Q improves muscle growth in old mice.

Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength

Abstract: Abstract Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength

Abstract: Abstract Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

The jam session between muscle stem cells and the extracellular matrix in the tissue microenvironment

Abstract: Skeletal muscle requires a highly orchestrated coordination between multiple cell types and their microenvironment to exert its function and to maintain its homeostasis and regenerative capacity. Over the past decades, significant advances, including lineage tracing and single-cell RNA sequencing, have contributed to identifying multiple muscle resident cell populations participating in muscle maintenance and repair. Among these populations, muscle stem cells (MuSC), also known as satellite cells, in response to stress or injury, are able to proliferate, fuse, and form new myofibers to repair the damaged tissue. These cells reside adjacent to the myofiber and are surrounded by a specific and complex microenvironment, the stem cell niche. Major components of the niche are extracellular matrix (ECM) proteins, able to instruct MuSC behavior. However, during aging and muscle-associated diseases, muscle progressively loses its regenerative ability, in part due to a dysregulation of ECM components. This review provides an overview of the composition and importance of the MuSC microenvironment. We discuss relevant ECM proteins and how their mutations or dysregulation impact young and aged muscle tissue or contribute to diseases. Recent discoveries have improved our knowledge about the ECM composition of skeletal muscle, which has helped to mimic the architecture of the stem cell niche and improved the regenerative capacity of MuSC. Further understanding about extrinsic signals from the microenvironment controlling MuSC function and innovative technologies are still required to develop new therapies to improve muscle repair.

The Role of Oxidative Stress in Skeletal Muscle Myogenesis and Muscle Disease

Abstract: The contractile activity, high oxygen consumption and metabolic rate of skeletal muscle cause it to continuously produce moderate levels of oxidant species, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). Under normal physiological conditions, there is a dynamic balance between the production and elimination of ROS/RNS. However, when the oxidation products exceed the antioxidant defense capacity, the body enters a state of oxidative stress. Myogenesis is an important process to maintain muscle homeostasis and the physiological function of skeletal muscle. Accumulating evidence suggests that oxidative stress plays a key role in myogenesis and skeletal muscle physiology and pathology. In this review, we summarize the sources of reactive oxygen species in skeletal muscle and the causes of oxidative stress and analyze the key role of oxidative stress in myogenesis. Then, we discuss the relationship between oxidative stress and muscle homeostasis and physiopathology. This work systematically summarizes the role of oxidative stress in myogenesis and muscle diseases and provides targets for subsequent antioxidant therapy and repair of inflammatory damage in noninflammatory muscle diseases.

The Notch signaling network in muscle stem cells during development, homeostasis, and disease

Abstract: Abstract Skeletal muscle stem cells have a central role in muscle growth and regeneration. They reside as quiescent cells in resting muscle and in response to damage they transiently amplify and fuse to produce new myofibers or self-renew to replenish the stem cell pool. A signaling pathway that is critical in the regulation of all these processes is Notch. Despite the major differences in the anatomical and cellular niches between the embryonic myotome, the adult sarcolemma/basement-membrane interphase, and the regenerating muscle, Notch signaling has evolved to support the context-specific requirements of the muscle cells. In this review, we discuss the diverse ways by which Notch signaling factors and other modifying partners are operating during the lifetime of muscle stem cells to establish an adaptive dynamic network.

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

Abstract: Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making "CR mimetics" of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging.

Ca2+ leak through ryanodine receptor 1 regulates thermogenesis in resting skeletal muscle

Abstract: Significance The evolution of mammals to use skeletal muscle as a source of heat allowed them to spread to all parts of the globe. The generation of heat requires increased adenosine triphosphate (ATP) hydrolysis in the resting muscle in a regulated manner, but how this mechanism works is unknown. The results suggest that mammals increase their RyR1 Ca2+ leak rate to amplify a basal ATP turnover rate at the sarcoplasmic reticulum Ca2+ pump that is higher than that of lower vertebrates. Muscle-based thermogenesis allows regulation of body temperature that is essential for life in mammals and provides a potential pathway for manipulating body weight or temperature by altering metabolic rate. Mammals rely on nonshivering thermogenesis (NST) from skeletal muscle so that cold temperatures can be tolerated. NST results from activity of the sarcoplasmic reticulum (SR) Ca2+ pump in skeletal muscle, but the mechanisms that regulate this activity are unknown. Here, we develop a single-fiber assay to investigate the role of Ca2+ leak through ryanodine receptor 1 (RyR1) to generate heat at the SR Ca2+ pump in resting muscle. By inhibiting a subpopulation of RyR1s in a single-fiber preparation via targeted delivery of ryanodine through transverse tubules, we achieve in-preparation isolation of RyR1 Ca2+ leak. This maneuver provided a critical increase in signal-to-noise of the SR-temperature-sensitive dye ER thermoyellow fluorescence signal from the fiber to allow detection of SR temperature changes as either RyR1 or SR Ca2+ pump activity was altered. We found that RyR1 Ca2+ leak raises cytosolic [Ca2+] in the local vicinity of the SR Ca2+ pump to amplify thermogenesis. Furthermore, gene-dose-dependent increases in RyR1 leak in RYR1 mutant mice result in progressive rises in leak-dependent heat, consistent with raised local [Ca2+] at the SR Ca2+ pump via RyR1 Ca2+ leak. We also show that basal RyR Ca2+ leak and the heat generated by the SR Ca2+ pump in the absence of RyR Ca2+ leak is greater in fibers from mice than from toads. The distinct function of RyRs and SR Ca2+ pump in endothermic mammals compared to ectothermic amphibians provides insights into the mechanisms by which mammalian skeletal muscle achieves thermogenesis at rest.

The role of SERCA and sarcolipin in adaptive muscle remodeling.

Abstract: Sarcolipin (SLN) is a small integral membrane protein that regulates the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pump. When bound to SERCA, SLN reduces the apparent Ca2+ affinity of SERCA and uncouples SERCA Ca2+ transport from its ATP consumption. As such, SLN plays a direct role in altering skeletal muscle relaxation and energy expenditure. Interestingly, the expression of SLN is dynamic during times of muscle adaptation, where large increases in SLN content are found in response to development, atrophy, overload and disease. Several groups have suggested that increases in SLN, especially in dystrophic muscle, are deleterious to muscle function and exacerbate already abhorrent intracellular Ca2+ levels. However, there is also significant evidence to show that increased SLN content is a beneficial adaptive mechanism which protects the SERCA pump and activates Ca2+ signaling and adaptive remodeling during times of cell stress. In this review, we first discuss the role for SLN in healthy muscle during both development and overload, where SLN has been shown to activate Ca2+ signaling to promote mitochondrial biogenesis, fibre type shifts and muscle hypertrophy. Then, with respect to muscle disease, we summarize the discrepancies in the literature as to whether SLN upregulation is adaptive or maladaptive in nature. This review is the first to offer the concept of SLN hormesis in muscle disease, wherein both too much and too little SLN are detrimental to muscle health. Finally, the underlying mechanisms which activate SLN upregulation are discussed, specifically acknowledging a potential positive feedback loop between SLN and Ca2+ signaling molecules.

Factors mediating exercise‐induced organ crosstalk

Abstract: Exercise activates a plethora of metabolic and signalling pathways in skeletal muscle and other organs causing numerous systemic beneficial metabolic effects. Thus, regular exercise may ameliorate and prevent the development of several chronic metabolic diseases. Skeletal muscle is recognized as an important endocrine organ regulating systemic adaptations to exercise. Skeletal muscle may mediate crosstalk with other organs through the release of exercise‐induced cytokines, peptides and proteins, termed myokines, into the circulation. Importantly, other tissues such as the liver and adipose tissue may also release cytokines and peptides in response to exercise. Hence, exercise‐released molecules are collectively called exerkines. Moreover, extracellular vesicles (EVs), in the form of exosomes or microvesicles, may carry some of the signals involved in tissue crosstalk. This review focuses on the role of factors potentially mediating crosstalk between muscle and other tissues in response to exercise.

Muscle mitochondrial energetics predicts mobility decline in well‐functioning older adults: The baltimore longitudinal study of aging

Abstract: Muscle mitochondrial dysfunction is associated with poor mobility in aging. Whether mitochondrial dysfunction predicts subsequent mobility decline is unknown.