期刊
FASEB JOURNAL
卷 35, 期 5, 页码 -出版社
WILEY
DOI: 10.1096/fj.202002675R
关键词
aging; cystathionine gamma-lyase; H2S; MEF2c; myogenesis; S-sulfhydration
资金
- Natural Sciences and Engineering Research Council of Canada [04051]
- Heart and Stroke Foundation of Canada [G-18-0022098]
Hydrogen sulfide (H2S) plays a crucial role in maintaining myogenesis and may serve as a potential candidate for preventing age-related sarcopenia and treating muscle injury.
Hydrogen sulfide (H2S) can be endogenously produced and belongs to the class of signaling molecules known as gasotransmitters. Cystathionine gamma-lyase (CSE)-derived H2S is implicated in the regulation of cell differentiation and the aging process, but the involvements of the CSE/H2S system in myogenesis upon aging and injury have not been explored. In this study, we demonstrated that CSE acts as a major H2S-generating enzyme in skeletal muscles and is significantly down-regulated in aged skeletal muscles in mice. CSE deficiency exacerbated the age-dependent sarcopenia and cardiotoxin-induced injury/regeneration in mouse skeletal muscle, possibly attributed to inefficient myogenesis. In contrast, supplement of NaHS (an H2S donor) induced the expressions of myogenic genes and promoted muscle regeneration in mice. In vitro, incubation of myoblast cells (C2C12) with H2S promoted myogenesis, as evidenced by the inhibition of cell cycle progression and migration, altered expressions of myogenic markers, elongation of myoblasts, and formation of multinucleated myotubes. Myogenesis was also found to upregulate CSE expression, while blockage of CSE/H2S signaling resulted in a suppression of myogenesis. Mechanically, H2S significantly induced the heterodimer formation between MEF2c and MRF4 and promoted the binding of MEF2c/MRF4 to myogenin promoter. MEF2c was S-sulfhydrated at both cysteine 361 and 420 in the C-terminal transactivation domain, and blockage of MEF2c S-sulfhydration abolished the stimulatory role of H2S on MEF2c/MRF4 heterodimer formation. These findings support an essential role for H2S in maintaining myogenesis, presenting it as a potential candidate for the prevention of age-related sarcopenia and treatment of muscle injury.
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