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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 -
American Journal of Physiology. Cell... Jun 2022Decreased skeletal muscle contractile activity (disuse) or unloading leads to muscle mass loss, also known as muscle atrophy. The balance between muscle protein... (Review)
Review
Decreased skeletal muscle contractile activity (disuse) or unloading leads to muscle mass loss, also known as muscle atrophy. The balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB) is the primary determinant of skeletal muscle mass. A reduced mechanical load on skeletal muscle is one of the main external factors leading to muscle atrophy. However, endocrine and inflammatory factors can act synergistically in catabolic states, amplifying the atrophy process and accelerating its progression. In addition, older individuals display aging-induced anabolic resistance, which can predispose this population to more pronounced effects when exposed to periods of reduced physical activity or mechanical unloading. Different cellular mechanisms contribute to the regulation of muscle protein balance during skeletal muscle atrophy. This review summarizes the effects of muscle disuse on muscle protein balance and the molecular mechanisms involved in muscle atrophy in the absence or presence of disease. Finally, a discussion of the current literature describing efficient strategies to prevent or improve the recovery from muscle atrophy is also presented.
Topics: Aging; Humans; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Muscular Disorders, Atrophic
PubMed: 35476500
DOI: 10.1152/ajpcell.00425.2021 -
American Journal of Physiology.... Sep 2014Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are... (Review)
Review
Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy. In the past 10 years much has been published about MuRF1 and MAFbx with respect to their mRNA expression patterns under atrophy-inducing conditions, their transcriptional regulation, and their putative substrates. However, much remains to be learned about the physiological role of both genes in the regulation of mass and other cellular functions in striated muscle. Although both MuRF1 and MAFbx are enriched in skeletal, cardiac, and smooth muscle, this review will focus on the current understanding of MuRF1 and MAFbx in skeletal muscle, highlighting the critical questions that remain to be answered.
Topics: Animals; Gene Expression Regulation; Humans; Mice; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Organ Size; Proteasome Endopeptidase Complex; SKP Cullin F-Box Protein Ligases; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 25096180
DOI: 10.1152/ajpendo.00204.2014 -
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 -
American Journal of Physiology.... Apr 2021Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic...
Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, whereas MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia. MOTS-c, a mitochondrial-derived peptide reduces high-fat-diet-induced muscle atrophy signaling by reducing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways play key roles in MOTS-c action on myostatin expression.
Topics: Adult; Aged; Aged, 80 and over; Animals; Cells, Cultured; Diet, High-Fat; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mitochondrial Proteins; Muscle, Skeletal; Muscular Atrophy; Myostatin; Palmitic Acid; Signal Transduction; Young Adult
PubMed: 33554779
DOI: 10.1152/ajpendo.00275.2020 -
Journal of Cachexia, Sarcopenia and... Aug 2019Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still...
BACKGROUND
Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exendin-4 (Ex-4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP-1R agonist for muscle wasting and the mechanisms involved.
METHODS
Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex-4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex-4 in a Dex-induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex-4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)-induced muscle atrophy model. Furthermore, we evaluated the effect of a long-acting GLP-1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J-mdx mice, a Duchenne muscular dystrophy model.
RESULTS
Ex-4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F-box only protein 32 (atrogin-1) and muscle RING-finger protein-1 (MuRF-1) in Dex-treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP-1R. In addition, Ex-4 treatment inhibited glucocorticoid receptor (GR) translocation by up-regulating the proteins of GR inhibitory complexes. In a Dex-induced muscle atrophy model, Ex-4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex-4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long-acting GLP-1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J-mdx mice.
CONCLUSIONS
GLP-1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP-1R-mediated signalling pathways. These novel findings suggest that activating GLP-1R signalling may be useful for the treatment of atrophy-related muscular diseases.
Topics: Animals; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Humans; Male; Mice; Muscular Atrophy; Sarcopenia; Transfection
PubMed: 31020810
DOI: 10.1002/jcsm.12434 -
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 -
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 -
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 -
Frontiers in Endocrinology 2021Sarcopenia, characterized by reduced muscle function as well as muscle mass, has been a public health problem with increasing prevalence. It might result from aging,...
Sarcopenia, characterized by reduced muscle function as well as muscle mass, has been a public health problem with increasing prevalence. It might result from aging, injury, hormone imbalance and other catabolic conditions. Recently, exosomes were considered to regulate muscle regeneration and protein synthesis. In order to confirm the effect of BMSC-derived exosomes (BMSC-Exos) on muscle, dexamethasone-induced muscle atrophy was built both and . In the present research, BMSC-Exos attenuated the decrease of myotube diameter induced by dexamethasone, indicating that BMSC-Exos played a protective role in skeletal muscle atrophy. Further mechanism analysis exhibited that the content of miR-486-5p in C2C12 myotubes was up-regulated after treated with BMSC-Exos. Meanwhile, BMSC-Exos markedly downregulated the nuclear translocation of FoxO1, which plays an important role in muscle differentiation and atrophy. Importantly, the miR-486-5p inhibitor reversed the decreased expression of FoxO1 induced by BMSC-Exos. In animal experiments, BMSC-Exos inhibited dexamethasone-induced muscle atrophy, and miR-486-5p inhibitor reversed the protective effect of BMSC-Exos. These results indicating that BMSC-derived exosomes inhibit dexamethasone-induced muscle atrophy miR486-5p/Foxo1 Axis.
Topics: Animals; Cell Differentiation; Dexamethasone; Exosomes; Forkhead Box Protein O1; Mesenchymal Stem Cells; Mice; MicroRNAs; Muscular Atrophy; Signal Transduction
PubMed: 34659106
DOI: 10.3389/fendo.2021.681267