Cystathionine gamma‐lyase/H₂S signaling facilitates myogenesis under aging and injury condition

Abstract

Hydrogen sulfide (H 2 S) can be endogenously produced and belongs to the class of signaling molecules known as gasotransmitters. Cystathionine gamma-lyase (CSE)-derived H 2 S is implicated in the regulation of cell differentiation and the aging process, but the involvements of the CSE/H 2 S system in myogenesis upon aging and injury have not been explored. In this study, we demonstrated that CSE acts as a major H 2 S-generating enzyme in skeletal muscles and is significantly downregulated in aged skeletal muscles in mice. CSE deficiency exacerbated the agedependent sarcopenia and cardiotoxin-induced injury/regeneration in mouse skeletal muscle, possibly attributed to inefficient myogenesis. In contrast, supplement of NaHS (an H 2 S donor) induced the expressions of myogenic genes and promoted muscle regeneration in mice. In vitro, incubation of myoblast cells (C2C12) with H 2 S 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/H 2 S signaling resulted in a suppression of myogenesis. Mechanically, H 2 S 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 H 2 S on MEF2c/MRF4 heterodimer formation. These findings support an essential role for H 2 S in maintaining myogenesis, presenting it as a potential candidate for the prevention of age-related sarcopenia and treatment of muscle injury.

BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cells

“…3 H). Furthermore, the regions of open chromatin in Bmal1 –/– cells include previously annotated enhancer regions, identified by the presence of H3K27ac ( Blum et al 2012 ), which promote the transcription of genes that facilitate myogenesis in injured muscle (e.g., Cystathionin γ-lyse [ Cth ]) ( Zhang et al 2021 ) or participate in early myogenesis (e.g., Mylk4 ) ( Fig. 3 I; Shang et al 2020 ).…”

H2S Protects Against Immobilization-Induced Muscle Atrophy via Reducing Oxidative Stress and Inflammation

“…Both chronic inflammatory reaction and oxidative stress have been already proposed in the pathogenesis of skeletal muscle atrophy due to different etiologies ( Moylan and Reid, 2007 ; Meng and Yu, 2010 ). Previous studies have shown that administration of H 2 S donor NaHS can alleviate skeletal muscle atrophy induced by type 2 diabetes ( Bitar et al, 2018 ), hyperhomocysteinemia ( Majumder et al, 2018 ), ventilator ( Ichinoseki-Sekine et al, 2021 ), cardiotoxin ( Zhang et al, 2021 ), and denervation ( Kuo et al, 2015 ) by attenuating inflammation, oxidative stress and protein degradation. The present study demonstrated that treatment with either slow (GYY4137) or rapid (NaHS) H 2 S releasing donors protected mice against immobilization-induced muscle atrophy.…”

CTH/H2S Regulates LPS-Induced Inflammation through IL-8 Signaling in MAC-T Cells

“…In addition, CBS, 3-MST and CAT are also involved in producing H 2 S [ 27 ]. The CTH/H 2 S system plays a part in both health and diseases, and is implicated in the regulation of multiple physiological and pathological effects, including inflammation, immune response, cell differentiation, cancer, aging and the injury process [ 6 , 13 , 16 ].…”

“…These enzymes are widely distributed in mammalian tissues, including the liver, kidney, retina and spleen, and are induced by external stimulation and the intracellular environment [ 15 ]. The CTH/H 2 S system plays a part in both health and diseases, and CTH-derived H 2 S is implicated in the regulation of multiple signal physiological effects, including immune response, cell differentiation, cancer, aging and the injury process [ 6 , 16 ]. In addition, Cys, a non-essential amino acid with a nonpolar sulfhydryl group (-SH), is abundant in milk, and provides many substrates for endogenous H 2 S synthesis [ 17 ].…”