Role of Exercise in Skeletal Muscle Atrophy: A Mechanistic Investigation

PURPOSE: Skeletal muscle atrophy induces overall health problems and many related diseases in older adults. In particular, sarcopenia is related to lowered quality of life, decreased physical activity, high levels of morbidity and mortality owing to chronic diseases, and even falling. Despite the many clinical studies on skeletal muscle atrophy, a little study had been about the exact mechanism of skeletal muscle atrophy at the molecular level. In 2017, A disease code (ICD-10-CM) for skeletal muscle atrophy related to sarcopenia was announced to attempt a clinical approach in the United States. According to these approaches, non-invasive clinical treatment is the most effective method for treating skeletal muscle atrophy. The purpose of this study was to analyze the molecular mechanisms of muscular exercise and related skeletal muscle atrophy factors.METHODS: This systemic review focused on skeletal muscle atrophy and muscular exercise. The keywords were used on “MeSH: muscle atrophy OR skeletal muscle atrophy OR muscle OR atrophy AND physical exercise OR exercise OR exercise training” for English and Korean. This paper searched PubMED, OVIDMEDLINE, and EMBASE for literature consideration.RESULTS: Skeletal muscle atrophy was related to a complex molecular network, and exercise affects IGF-1/Akt/mTOR signaling. The related skeletal muscle atrophy factors were evaluated as MurF1, MAFbx, IGF-1, and NFkB. We proposed new related factors such as ATF 4, Gadd45a, and p21; however, the results related to exercise were not shown in recent studies.CONCLUSIONS: In conclusion, we identified skeletal muscle atrophy factors at the molecular level of muscle physiology, and these new factors may become an interesting field of study in clinical human trial and animal studies.

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Physiology of a Microgravity Environment Invited Review: Microgravity and skeletal muscle

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.2.823 ◽

2000 ◽

Vol 89 (2) ◽

pp. 823-839 ◽

Cited By ~ 332

Author(s):

Robert H. Fitts ◽

Danny R. Riley ◽

Jeffrey J. Widrick

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Thin Filament ◽

Molecular Mechanisms ◽

Skeletal Muscle Atrophy ◽

Microgravity Environment ◽

Type I ◽

Fiber Types ◽

Maximal Velocity ◽

Cross Sectional

Spaceflight (SF) has been shown to cause skeletal muscle atrophy; a loss in force and power; and, in the first few weeks, a preferential atrophy of extensors over flexors. The atrophy primarily results from a reduced protein synthesis that is likely triggered by the removal of the antigravity load. Contractile proteins are lost out of proportion to other cellular proteins, and the actin thin filament is lost disproportionately to the myosin thick filament. The decline in contractile protein explains the decrease in force per cross-sectional area, whereas the thin-filament loss may explain the observed postflight increase in the maximal velocity of shortening in the type I and IIa fiber types. Importantly, the microgravity-induced decline in peak power is partially offset by the increased fiber velocity. Muscle velocity is further increased by the microgravity-induced expression of fast-type myosin isozymes in slow fibers (hybrid I/II fibers) and by the increased expression of fast type II fiber types. SF increases the susceptibility of skeletal muscle to damage, with the actual damage elicited during postflight reloading. Evidence in rats indicates that SF increases fatigability and reduces the capacity for fat oxidation in skeletal muscles. Future studies will be required to establish the cellular and molecular mechanisms of the SF-induced muscle atrophy and functional loss and to develop effective exercise countermeasures.

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MuRF1/TRIM63, Master Regulator of Muscle Mass

International Journal of Molecular Sciences ◽

10.3390/ijms21186663 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6663 ◽

Cited By ~ 1

Author(s):

Dulce Peris-Moreno ◽

Daniel Taillandier ◽

Cécile Polge

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Muscle Wasting ◽

Skeletal Muscle Atrophy ◽

Cardiac Functions ◽

Important Player ◽

Cardiac Muscles ◽

Inhibitory Molecules

The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies.

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Molecular mechanisms of skeletal muscle atrophy

10.17077/etd.j885bs6n ◽

2012 ◽

Author(s):

Scott Matthew Ebert

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Skeletal Muscle Atrophy

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Skeletal muscle denervation causes skeletal muscle atrophy through a pathway that involves both Gadd45a and HDAC4

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00380.2013 ◽

2013 ◽

Vol 305 (7) ◽

pp. E907-E915 ◽

Cited By ~ 67

Author(s):

Kale S. Bongers ◽

Daniel K. Fox ◽

Scott M. Ebert ◽

Steven D. Kunkel ◽

Michael C. Dyle ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Muscle Fiber ◽

Molecular Mechanisms ◽

Skeletal Muscle Atrophy ◽

Muscle Denervation ◽

Mrna Induction ◽

Convergence Point ◽

Muscle Fiber Atrophy ◽

Fiber Atrophy

Skeletal muscle denervation causes muscle atrophy via complex molecular mechanisms that are not well understood. To better understand these mechanisms, we investigated how muscle denervation increases growth arrest and DNA damage-inducible 45α ( Gadd45a) mRNA in skeletal muscle. Previous studies established that muscle denervation strongly induces Gadd45a mRNA, which increases Gadd45a, a small myonuclear protein that is required for denervation-induced muscle fiber atrophy. However, the mechanism by which denervation increases Gadd45a mRNA remained unknown. Here, we demonstrate that histone deacetylase 4 (HDAC4) mediates induction of Gadd45a mRNA in denervated muscle. Using mouse models, we show that HDAC4 is required for induction of Gadd45a mRNA during muscle denervation. Conversely, forced expression of HDAC4 is sufficient to increase skeletal muscle Gadd45a mRNA in the absence of muscle denervation. Moreover, Gadd45a mediates several downstream effects of HDAC4, including induction of myogenin mRNA, induction of mRNAs encoding the embryonic nicotinic acetylcholine receptor, and, most importantly, skeletal muscle fiber atrophy. Because Gadd45a induction is also a key event in fasting-induced muscle atrophy, we tested whether HDAC4 might also contribute to Gadd45a induction during fasting. Interestingly, however, HDAC4 is not required for fasting-induced Gadd45a expression or muscle atrophy. Furthermore, activating transcription factor 4 (ATF4), which contributes to fasting-induced Gadd45a expression, is not required for denervation-induced Gadd45a expression or muscle atrophy. Collectively, these results identify HDAC4 as an important regulator of Gadd45a in denervation-induced muscle atrophy and elucidate Gadd45a as a convergence point for distinct upstream regulators during muscle denervation and fasting.

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Skeletal Muscle Atrophy: Discovery of Mechanisms and Potential Therapies

Physiology ◽

10.1152/physiol.00003.2019 ◽

2019 ◽

Vol 34 (4) ◽

pp. 232-239 ◽

Cited By ~ 15

Author(s):

Scott M. Ebert ◽

Asma Al-Zougbi ◽

Sue C. Bodine ◽

Christopher M. Adams

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Signaling Network ◽

Skeletal Muscle Atrophy ◽

Molecular Signaling ◽

Molecular Signaling Network

Skeletal muscle atrophy proceeds through a complex molecular signaling network that is just beginning to be understood. Here, we discuss examples of recently identified molecular mechanisms of muscle atrophy and how they highlight an immense need and opportunity for focused biochemical investigations and further unbiased discovery work.

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Thyroid Hormone Action in Muscle Atrophy

Metabolites ◽

10.3390/metabo11110730 ◽

2021 ◽

Vol 11 (11) ◽

pp. 730

Author(s):

Maria Angela De Stefano ◽

Raffaele Ambrosio ◽

Tommaso Porcelli ◽

Gianfranco Orlandino ◽

Domenico Salvatore ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Thyroid Hormone ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Muscle Protein ◽

Active Form ◽

Skeletal Muscle Atrophy ◽

Target Tissue ◽

Muscle Mass Loss

Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin–proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in muscle, deiodinases type 2 (D2) and type 3 (D3) are both present. D2 activates the prohormone T4 into the active form triiodothyronine (T3), whereas D3 inactivates both T4 and T3 by the removal of an inner ring iodine. Here we will review the present knowledge of TH action in skeletal muscle atrophy, in particular, on the molecular mechanisms presiding over the control of intracellular T3 concentration in wasting muscle conditions. Finally, we will discuss the possibility of exploiting the modulation of deiodinases as a possible therapeutic approach to treat muscle atrophy.

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The Molecular Mechanisms of Calpains Action on Skeletal Muscle Atrophy

Physiological Research ◽

10.33549/physiolres.933087 ◽

2016 ◽

pp. 547-560 ◽

Cited By ~ 24

Author(s):

J. HUANG ◽

X. ZHU

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Molecular Mechanisms ◽

Muscle Protein ◽

Therapeutic Interventions ◽

Skeletal Muscle Atrophy ◽

Akt Phosphorylation ◽

Downstream Effects ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

Skeletal muscle atrophy is associated with a loss of muscle protein which may result from both increased proteolysis and decreased protein synthesis. Investigations on cell signaling pathways that regulate muscle atrophy have promoted our understanding of this complicated process. Emerging evidence implicates that calpains play key roles in dysregulation of proteolysis seen in muscle atrophy. Moreover, studies have also shown that abnormally activated calpain results muscle atrophy via its downstream effects on ubiquitin-proteasome pathway (UPP) and Akt phosphorylation. This review will discuss the role of calpains in regulation of skeletal muscle atrophy mainly focusing on its collaboration with either UPP or Akt in atrophy conditions in hope to stimulate the interest in development of novel therapeutic interventions for skeletal muscle atrophy.

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A mini review: Proteomics approaches to understand disused vs. exercised human skeletal muscle

Physiological Genomics ◽

10.1152/physiolgenomics.00043.2018 ◽

2018 ◽

Vol 50 (9) ◽

pp. 746-757 ◽

Cited By ~ 4

Author(s):

Yoshitake Cho ◽

Robert S. Ross

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Atrophy ◽

Human Skeletal Muscle ◽

Molecular Mechanisms ◽

Bed Rest ◽

Skeletal Muscle Atrophy ◽

Direct Result ◽

Muscle Disorders ◽

Exercise Induced

Immobilization, bed rest, or denervation leads to muscle disuse and subsequent skeletal muscle atrophy. Muscle atrophy can also occur as a component of various chronic diseases such as cancer, AIDS, sepsis, diabetes, and chronic heart failure or as a direct result of genetic muscle disorders. In addition to this atrophic loss of muscle mass, metabolic deregulation of muscle also occurs. In contrast, physical exercise plays a beneficial role in counteracting disuse-induced atrophy by increasing muscle mass and strength. Along with this, exercise can also reduce mitochondrial dysfunction and metabolic deregulation. Still, while exercise causes valuable metabolic and functional adaptations in skeletal muscle, the mechanisms and effectors that lead to these changes such as increased mitochondria content or enhanced protein synthesis are not fully understood. Therefore, mechanistic insights may ultimately provide novel ways to treat disuse induced atrophy and metabolic deregulation. Mass spectrometry (MS)-based proteomics offers enormous promise for investigating the molecular mechanisms underlying disuse and exercise-induced changes in skeletal muscle. This review will focus on initial findings uncovered by using proteomics approaches with human skeletal muscle specimens and discuss their potential for the future study.

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Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012095 ◽

2020 ◽

Vol 295 (9) ◽

pp. 2787-2803 ◽

Cited By ~ 8

Author(s):

Scott M. Ebert ◽

Steven A. Bullard ◽

Nathan Basisty ◽

George R. Marcotte ◽

Zachary P. Skopec ◽

...

Keyword(s):

Skeletal Muscle ◽

Transcription Factor ◽

Muscle Atrophy ◽

Molecular Level ◽

Muscle Fibers ◽

Skeletal Muscle Atrophy ◽

Skeletal Muscle Fibers ◽

Activating Transcription Factor 4 ◽

Activating Transcription Factor ◽

Transcription Factor 4

Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo. Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein β (C/EBPβ), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4–C/EBPβ heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF–C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBPβ, and the ATF–C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.

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