Abstract
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 (H2 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 H2 S donor). The results suggested multi-organ damage by HHcy in the CBS+/- mouse strain compared with WT control mice (CBS+/+ ). H2 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 H2 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, H2 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 H2 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 H2 S. The bone and muscle strengths were found to be decreased in the CBS+/- mice but the H2 S treatment normalized skeletal muscle strength in the CBS+/- mice. Our findings suggest that H2 S mitigates the mitophagy-led skeletal muscle remodeling via epigenetic regulation of the gene writer and eraser function.