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Review
. 2021 Dec 24:9:785712.
doi: 10.3389/fcell.2021.785712. eCollection 2021.

Regulation of Myostatin on the Growth and Development of Skeletal Muscle

Ming-Ming Chen  1 , Yi-Ping Zhao  2 , Yue Zhao  1 , Shou-Long Deng  3 , Kun Yu  1
Affiliations
Review

Regulation of Myostatin on the Growth and Development of Skeletal Muscle

Ming-Ming Chen et al. Front Cell Dev Biol. .

Abstract

Myostatin (MSTN), a member of the transforming growth factor-β superfamily, can negatively regulate the growth and development of skeletal muscle by autocrine or paracrine signaling. Mutation of the myostatin gene under artificial or natural conditions can lead to a significant increase in muscle quality and produce a double-muscle phenotype. Here, we review the similarities and differences between myostatin and other members of the transforming growth factor-β superfamily and the mechanisms of myostatin self-regulation. In addition, we focus extensively on the regulation of myostatin functions involved in myogenic differentiation, myofiber type conversion, and skeletal muscle protein synthesis and degradation. Also, we summarize the induction of reactive oxygen species generation and oxidative stress by myostatin in skeletal muscle. This review of recent insights into the function of myostatin will provide reference information for future studies of myostatin-regulated skeletal muscle formation and may have relevance to agricultural fields of study.

Keywords: degradation; myogenesis; myostatin; protein synthesis; skeletal muscle development.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Myostatin and its signaling pathway are involved in myogenesis. The myostatin dimer first binds to ActRIIB, then to ALK4/5 to form a complex; Smad2/3/4 enters the nucleus to regulate the expression of target genes. Different transcription factors bind to the Smad2/3/4 complex, resulting in various functions of the Smad signaling pathway. Smad7 can prevent the phosphorylation of R-Smad by ActRI, thus blocking the myostatin signaling pathway mediated by Smad. The nonclassical pathway of myostatin signaling involves the PI3K/Akt/mTOR and MAPK signaling pathways, the latter of which mainly includes ERKs, JNKs, and p38MAPK. All of these pathways mediate the transcription of myogenic regulatory factors (myogenin, Myf5, MyoD), MuRF-1, and atrogin-1 to regulate myogenic differentiation and skeletal muscle quality. ActRIIB: activin receptor kinases II-B; ALK4/5: activin receptor-like kinase 4/5; R-Smad: receptor-regulated Smad; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; Myf5: myogenic factor 5; MyoD: myoblast determination protein 1; MuRF-1: muscle RING-finger protein-1.
FIGURE 2
FIGURE 2
Potential mechanism of myostatin-induced ROS generation in skeletal muscle. In the presence of Smad3, increased myostatin induces TNF-α production via NF-κB signaling, increasing the production of ROS by NADPH oxidase. The induced ROS cause a feed forward loop, further increasing myostatin levels via NF-κB signaling of TNF-α. In the absence of Smad3, myostatin induces TNF-α and IL-6 to activate p38 and ERK MAPKs to promote Nox- and XO-mediated ROS generation. The induced ROS result in increased C/EBP homologous protein (CHOP) levels and up-regulation of MuRF-1 transcription. An increased CHOP protein level in turn induces ROS production that further leads to increased myostatin production. TNF-α: tumor necrosis factor alpha; ROS: reactive oxygen species; NF-κB: nuclear factor-κB; IL-6: interleukin 6; Nox: NADPH oxidase; XO: xanthine oxidase; C/EBP: CCAAT/enhancer-binding protein.
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