The role of the circadian clock system in mitochondrial trans-sulfuration pathway and tissue remodeling

Hydrogen sulfide (H2S) is a product of epigenetics that involves trans-sulfuration pathway for clearance of homocysteine (Hcy), thereby mitigating skeletal muscle's pathological remodeling. Although master circadian clock regulator that is known as brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (i.e., BMAL1) is associated with S-adenosylhomocysteine hydrolase and Hcy metabolism but how trans-sulfuration is influenced by circadian clock remains unexplored. We hypothesize that alterations in functioning of circadian clock during sleep/wake cycle affect skeletal muscle. To test this, we measured MMP-2 and MMP-9. We also studied MMP-13 that is influenced by growth arrest and DNA damage-45 during sleep/wake cycle. Wild type and cystathionine β synthase deficient (CBS-/+) mice were treated with H2S and subjected for measurement of trans-sulfuration factors from skeletal muscle. Results suggested robust activation of MMPs in wake mice versus sleep indicating "1-carbon metabolic dysregulation" which takes place during muscular dystrophy. Interestingly, levels of CBS, cystathionine γ lyase, MTHFR, phosphatidylethanolamine N-methyltransferase, and Hcy-protein bound paraoxonase 1 were attenuated CBS-/+. H2S treatment mitigated the changes. Levels of mitochondrial peroxisome proliferator-activated receptor-gamma coactivator 1-α and mitofusin-2 were improved by H2S. Our findings suggest participation of circadian clock in trans-sulfuration pathway that affects skeletal muscle and mitochondrial regeneration.