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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 -
Biomolecules Oct 2019Sarcopenia is characterized by a loss of muscle mass, quality, and function, and negatively impacts health, functionality, and quality of life for numerous populations,... (Review)
Review
Sarcopenia is characterized by a loss of muscle mass, quality, and function, and negatively impacts health, functionality, and quality of life for numerous populations, particularly older adults. Creatine is an endogenously produced metabolite, which has the theoretical potential to counteract many of the morphological and metabolic parameters underpinning sarcopenia. This can occur through a range of direct and indirect mechanisms, including temporal and spatial functions that accelerate ATP regeneration during times of high energy demand, direct anabolic and anti-catabolic functions, and enhanced muscle regenerating capacity through positively impacting muscle stem cell availability. Studies conducted in older adults show little benefit of creatine supplementation alone on muscle function or mass. In contrast, creatine supplementation as an adjunct to exercise training seems to augment the muscle adaptive response to the training stimulus, potentially through increasing capacity for higher intensity exercise, and/or by enhancing post-exercise recovery and adaptation. As such, creatine may be an effective dietary strategy to combat age-related muscle atrophy and sarcopenia when used to complement the benefits of exercise training.
Topics: Aged; Aging; Animals; Creatine; Dietary Supplements; Exercise; Humans; Muscular Atrophy
PubMed: 31652853
DOI: 10.3390/biom9110642 -
Mitochondrial dysfunction and skeletal muscle atrophy: Causes, mechanisms, and treatment strategies.Mitochondrion Sep 2023Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in... (Review)
Review
Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.
Topics: Humans; Cachexia; Muscular Atrophy; Muscle, Skeletal; Mitochondria; Antioxidants
PubMed: 37451353
DOI: 10.1016/j.mito.2023.07.003 -
British Journal of Pharmacology Aug 2021Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium...
BACKGROUND AND PURPOSE
Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy.
EXPERIMENTAL APPROACH
The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test.
KEY RESULTS
Triptolide (10-100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml )-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes. In LPS (1 mg·kg , i.p.)-challenged mice, triptolide (5 and 20 μg·kg ·day , i.p.) decreased plasma TNF-α levels and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion.
CONCLUSIONS AND IMPLICATIONS
These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.
Topics: Animals; Diterpenes; Epoxy Compounds; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Phenanthrenes; Tumor Necrosis Factor-alpha
PubMed: 33788266
DOI: 10.1111/bph.15472 -
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 -
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 -
Journal of Translational Medicine Jul 2023Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological... (Review)
Review
Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-β-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.
Topics: Humans; Phosphatidylinositol 3-Kinases; Muscular Atrophy; Muscle, Skeletal; Mitochondria; Signal Transduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 37495991
DOI: 10.1186/s12967-023-04369-z -
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 -
Journal of Cachexia, Sarcopenia and... Feb 2023Cisplatin (CP) is a widely used chemotherapeutic drug with subsequent adverse effects on different organs and tissues including skeletal muscle loss and atrophy as the...
BACKGROUND
Cisplatin (CP) is a widely used chemotherapeutic drug with subsequent adverse effects on different organs and tissues including skeletal muscle loss and atrophy as the most common clinical symptoms. The molecular mechanism of cisplatin-induced muscle atrophy is not clearly understood. However, recent significant advances indicate that it is related to an imbalance in both the protein status and apoptosis. Capsaicin (CAP) is one of the major ingredients in chilli peppers. It is a valuable pharmacological agent with several therapeutic applications in controlling pain and inflammation with particular therapeutic potential in muscle atrophy. However, the mechanisms underlying its protective effects against cisplatin-induced muscle loss and atrophy remain largely unknown. This study aims to investigate capsaicin's beneficial effects on cisplatin-induced muscle loss and atrophy in vitro and in vivo.
METHODS
The anti-muscle-atrophic effect of capsaicin on cisplatin-induced muscle loss was investigated using in vivo and in vitro studies. By using the pretreatment model, pretreated capsaicin for 24 h and treated with cisplatin for 48 h, we utilized a C C myotube formation model where cell viability analysis, immunofluorescence, and protein expression were measured to investigate the effect of capsaicin in hampering cisplatin-induced muscle atrophy. C57BL/6 mice were administered capsaicin (10, 40 mg/kg BW) as a pretreatment for 5 weeks and cisplatin (3 mg/kg BW) for seven consecutively days to assess muscle atrophy in an animal model for protein and oxidative stress examination, and the grip strength was tested to evaluate the muscle strength.
RESULTS
Our study results indicated that cisplatin caused lower cell viability and showed a subset of hallmark signs typically recognized during atrophy, including severe reduction in the myotube diameter, repression of Akt, and mTOR protein expression. However, pretreatment with capsaicin could ameliorate cisplatin-induced muscle atrophy by up-regulating the protein synthesis in skeletal muscle as well as down-regulating the markers of protein degradation. Additionally, capsaicin was able to downregulate the protein expression of apoptosis-related markers, activated TRPV1 and autophagy progress modulation and the recovery of lysosome function. In vivo, capsaicin could relieve oxidative stress and cytokine secretion while modulating autophagy-related lysosome fusion, improving grip strength, and alleviating cisplatin-induced body weight loss and gastrocnemius atrophy.
CONCLUSIONS
These findings suggest that capsaicin can restore cisplatin-induced imbalance between protein synthesis and protein degradation pathways and it may have protective effects against cisplatin-induced muscle atrophy.
Topics: Animals; Mice; Capsaicin; Cisplatin; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Atrophy
PubMed: 36401337
DOI: 10.1002/jcsm.13120 -
Advanced Science (Weinheim,... Jun 2023Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are...
Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.
Topics: Mice; Animals; RNA, Circular; Muscular Atrophy; DNA-Binding Proteins; DNA, Mitochondrial; Mitochondria
PubMed: 37088818
DOI: 10.1002/advs.202206732