Hydrogen sulfide mitigates skeletal muscle mitophagy‐led tissue remodeling via epigenetic regulation of the gene writer and eraser function

Ketone bodies (KB) serve as the food for mitochondrial biogenetics. Interestingly, probiotics are known to promote KB formation in the gut (especially those that belong to the Lactobacillus genus). Furthermore, Lactobacillus helps produce folate that lowers the levels of homocysteine (Hcy); a hallmark non‐proteinogenic amino acid that defines the importance of epigenetics, and its landscape. In this study, we decided to test whether hydrogen sulfide (H(2)S), another Hcy lowering agent regulates the epigenetic gene writer DNA methyltransferase (DNMT), eraser FTO and TET2, and thus mitigates the skeletal muscle remodeling. We treated hyperhomocysteinemic (HHcy, cystathionine beta‐synthase heterozygote knockout; CBS(+/−)) mice with NaHS (the H(2)S donor). The results suggested multi‐organ damage by HHcy in the CBS(+/−)mouse strain compared with WT control mice (CBS(+/+)). H(2)S treatment abrogated most of the HHcy‐induced damage. The levels of gene writer (DNMT2) and H3K9 (methylation) were higher in the CBS(+/−) mice, and the H(2)S treatment normalized their levels. More importantly, the levels of eraser FTO, TET, and associated GADD45, and MMP‐13 were decreased in the CBS(+/−) mice; however, H(2)S treatment mitigated their respective decrease. These events were associated with mitochondrial fission, i.e., an increase in DRP1, and mitophagy. Although the MMP‐2 level was lower in CBS(+/−) compared to WT but H(2)S could further lower it in the CBS(+/−) mice. The MMPs levels were associated with an increase in interstitial fibrosis in the CBS(+/−) skeletal muscle. Due to fibrosis, the femoral artery blood flow was reduced in the CBS(+/−) mice, and that was normalized by H(2)S. The bone and muscle strengths were found to be decreased in the CBS(+/−) mice but the H(2)S treatment normalized skeletal muscle strength in the CBS(+/−) mice. Our findings suggest that H(2)S mitigates the mitophagy‐led skeletal muscle remodeling via epigenetic regulation of the gene writer and eraser function.