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Pharmacological Research Oct 2021Skeletal muscle is a crucial tissue for movement, gestural assistance, metabolic homeostasis, and thermogenesis. It makes up approximately 40% of the total body weight... (Review)
Review
Skeletal muscle is a crucial tissue for movement, gestural assistance, metabolic homeostasis, and thermogenesis. It makes up approximately 40% of the total body weight and 50% of total protein. However, several pathological abnormalities (e.g., chronic diseases, cancer, long-term infection, aging) can induce an imbalance in skeletal muscle protein synthesis and degradation, which triggers muscle wasting and even leads to atrophy. Skeletal muscle atrophy is characterized by weakening, shrinking, and decreasing muscle mass and fiber cross-sectional area at the histological level. It manifests as a reduction in force production, easy fatigue and decreased exercise capability, along with a lower quality of life. Mechanistically, there are several pathophysiological processes involved in skeletal muscle atrophy, including oxidative stress and inflammation, which then activate signal transduction, such as the ubiquitin proteasome system, autophagy lysosome system, and mTOR. Considering the great economic and social burden that muscle atrophy can inflict, effective prevention and treatment strategies are essential but still limited. Exercise is widely acknowledged as the most effective therapy for skeletal muscle atrophy; unfortunately, it is not applicable for all patients. Several active substances for skeletal muscle atrophy have been discovered and evaluated in clinical trials, however, they have not been marketed to date. Knowledge is being gained on the underlying mechanisms, highlighting more promising treatment strategies in the future. In this paper, the mechanisms and treatment strategies for skeletal muscle atrophy are briefly reviewed.
Topics: Animals; Humans; Muscle, Skeletal; Muscular Atrophy
PubMed: 34389456
DOI: 10.1016/j.phrs.2021.105807 -
The FEBS Journal Sep 2013Skeletal muscle mass increases during postnatal development through a process of hypertrophy, i.e. enlargement of individual muscle fibers, and a similar process may be... (Review)
Review
Skeletal muscle mass increases during postnatal development through a process of hypertrophy, i.e. enlargement of individual muscle fibers, and a similar process may be induced in adult skeletal muscle in response to contractile activity, such as strength exercise, and specific hormones, such as androgens and β-adrenergic agonists. Muscle hypertrophy occurs when the overall rates of protein synthesis exceed the rates of protein degradation. Two major signaling pathways control protein synthesis, the IGF1-Akt-mTOR pathway, acting as a positive regulator, and the myostatin-Smad2/3 pathway, acting as a negative regulator, and additional pathways have recently been identified. Proliferation and fusion of satellite cells, leading to an increase in the number of myonuclei, may also contribute to muscle growth during early but not late stages of postnatal development and in some forms of muscle hypertrophy in the adult. Muscle atrophy occurs when protein degradation rates exceed protein synthesis, and may be induced in adult skeletal muscle in a variety of conditions, including starvation, denervation, cancer cachexia, heart failure and aging. Two major protein degradation pathways, the proteasomal and the autophagic-lysosomal pathways, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These pathways involve a variety of atrophy-related genes or atrogenes, which are controlled by specific transcription factors, such as FoxO3, which is negatively regulated by Akt, and NF-κB, which is activated by inflammatory cytokines.
Topics: Animals; Humans; Muscle, Skeletal; Muscular Atrophy; Signal Transduction
PubMed: 23517348
DOI: 10.1111/febs.12253 -
The International Journal of... Oct 2013Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an... (Review)
Review
Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
Topics: Animals; Glucocorticoids; Humans; Muscular Atrophy; Protein Biosynthesis; Signal Transduction
PubMed: 23806868
DOI: 10.1016/j.biocel.2013.05.036 -
Disease Models & Mechanisms Jan 2013Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are... (Review)
Review
Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.
Topics: Animals; Autophagy; Cytokines; Homeostasis; Humans; Inflammation Mediators; Lysosomes; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myostatin; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-akt; Signal Transduction; Ubiquitin
PubMed: 23268536
DOI: 10.1242/dmm.010389 -
Ageing Research Reviews Sep 2013Situations such as the recovery from injury and illness can lead to enforced periods of muscle disuse or unloading. Such circumstances lead to rapid skeletal muscle... (Review)
Review
Situations such as the recovery from injury and illness can lead to enforced periods of muscle disuse or unloading. Such circumstances lead to rapid skeletal muscle atrophy, loss of functional strength and a multitude of related negative health consequences. The elderly population is particularly vulnerable to the acute challenges of muscle disuse atrophy. Any loss of skeletal muscle mass must be underpinned by a chronic imbalance between muscle protein synthesis and breakdown rates. It is recognized that muscle atrophy during prolonged (>10 days) disuse is brought about primarily by declines in post-absorptive and post-prandial muscle protein synthesis rates, without a clear contribution from changes in muscle protein breakdown. Few data are available on the impact of short-term disuse (<10 days) on muscle protein turnover in humans. However, indirect evidence indicates that considerable muscle atrophy occurs during this early phase, and is likely attributed to a rapid increase in muscle protein breakdown accompanied by the characteristic decline in muscle protein synthesis. Short-term disuse atrophy is of particular relevance in the development of sarcopenia, as it has been suggested that successive short periods of muscle disuse, due to sickness or injury, accumulate throughout an individual's lifespan and contributes considerably to the net muscle loss observed with aging. Research is warranted to elucidate the physiological and molecular basis for rapid muscle loss during short periods of disuse. Such mechanistic insight will allow the characterization of nutritional, exercise and/or pharmacological interventions to prevent or attenuate muscle loss during periods of disuse and therefore aid in the treatment of age-related sarcopenia.
Topics: Aged; Aging; Humans; Muscle, Skeletal; Muscular Atrophy; Muscular Disorders, Atrophic; Sarcopenia
PubMed: 23948422
DOI: 10.1016/j.arr.2013.07.003 -
Nature May 2023Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer. Muscle atrophy...
Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength. An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the non-canonical NFĸB pathway and was dependent on NFκB-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatin M (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatin M receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R-NIK signalling mediates cancer-associated muscle atrophy in an OSM-OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss.
Topics: Animals; Mice; Cachexia; Muscle Fibers, Skeletal; Muscular Atrophy; Neoplasms; Xedar Receptor; Humans; Signal Transduction; Ligands; Receptors, Oncostatin M; Oncostatin M; NF-kappaB-Inducing Kinase
PubMed: 37165186
DOI: 10.1038/s41586-023-06047-y -
Biochemical Pharmacology Aug 2023Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle... (Review)
Review
Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.
Topics: Humans; Muscular Atrophy; Oxidative Stress; Muscle, Skeletal; Sarcopenia; Antioxidants; Chronic Disease
PubMed: 37331636
DOI: 10.1016/j.bcp.2023.115664 -
Advances in Experimental Medicine and... 2018Atrophy is a classical hallmark of an array of disorders that affect skeletal muscle, ranging from inherited dystrophies, acquired inflammatory myopathies, ageing... (Review)
Review
Atrophy is a classical hallmark of an array of disorders that affect skeletal muscle, ranging from inherited dystrophies, acquired inflammatory myopathies, ageing (sarcopenia) and critical illness (sepsis). The loss of muscle mass and function in these instances is associated with disability, poor quality of life and in some cases mortality. The mechanisms which underpin muscle atrophy are complex; however, significant research has demonstrated an important role for inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), mediated by the generation of reactive oxygen species (ROS) in muscle wasting. Moreover, activation of the transcription factor nuclear factor kappa B (NF-κB) is a key lynchpin in the overall processes that mediate muscle atrophy. The significance of NF-κB as a key regulator of muscle atrophy has been emphasised by several in vivo studies, which have demonstrated that NF-κB-targeted therapies can abrogate muscle atrophy. In this chapter, we will summarise current knowledge on the role of cytokines (TNF-α) and NF-κB in the loss of muscle mass and function and highlight perspectives towards future research and potential therapies to combat muscle atrophy.
Topics: Cytokines; Humans; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 30390256
DOI: 10.1007/978-981-13-1435-3_12 -
Advances in Experimental Medicine and... 2020The incidence of muscle atrophy is increasing with each passing year, which imposes a huge burden on the quality of life of patients. It is a public health issue that... (Review)
Review
The incidence of muscle atrophy is increasing with each passing year, which imposes a huge burden on the quality of life of patients. It is a public health issue that causes a growing concern around the world. Exercise is one of the key strategies to prevent and treat various diseases. Appropriate exercise is conducive to compensatory muscle hypertrophy, to improve muscle strength and elasticity, and to train muscle coordination, which is also beneficial to the recovery of skeletal muscle function and the regeneration of muscle cells. Sequelae of paralysis of patients with limb dyskinesia caused by muscle atrophy will be significantly alleviated after regular exercise therapy. Furthermore, exercise therapy can slow down or even reverse muscle atrophy. This article aims to introduce the characteristics of muscle atrophy and summarize the role and mechanism of exercise in the treatment of muscle atrophy in the existing studies, in order to further explore the mechanism of exercise to protect muscle atrophy and provide protection for patients with muscular atrophy.
Topics: Exercise; Humans; Muscle Strength; Muscle, Skeletal; Muscular Atrophy; Quality of Life
PubMed: 32342463
DOI: 10.1007/978-981-15-1792-1_17 -
Nutrients Apr 2022The present study aimed to investigate the effects of monotropein (MON) on improving dexamethasone (DEX)-induced muscle atrophy in mice and C2C12 mouse skeletal muscle...
The present study aimed to investigate the effects of monotropein (MON) on improving dexamethasone (DEX)-induced muscle atrophy in mice and C2C12 mouse skeletal muscle cells. The body weights, grip strengths, and muscle weights of mice were assessed. The histological change in the gastrocnemius tissues was also observed through H&E staining. The expression of myosin heavy chain (MyHC), muscle ring finger 1 (MuRF1), and muscle atrophy F-box (Atrogin1) and the phosphorylation of AKT, mTOR, and FOXO3a in the muscle tissues of mice and C2C12 myotubes were analyzed using Western blotting. MON improved muscle atrophy in mice and C2C12 myotubes by regulating catabolic states via the AKT/mTOR/FOXO3a signaling pathways, and enhanced muscle function by the increases of muscle mass and strength in mice. This suggests that MON could be used for the prevention and treatment of muscle atrophy in patients.
Topics: Dexamethasone; Humans; Iridoids; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases
PubMed: 35565825
DOI: 10.3390/nu14091859