Role of the Circadian Clock System in Trans-sulfuration Pathway and Tissue Remodeling

Abstract

Previous studies from our laboratory revealed that the gaseous molecule; hydrogen sulfide (H2S), a metabolic product of epigenetics which involves trans-sulfuration pathway for ensuring the metabolism and clearance of homocysteine (Hcy) from the body, helped mitigate the skeletal muscle’s pathological remodeling. Although the master circadian clock regulator that is known as the b rain and m uscle a ryl hydrocarbon receptor nuclear translocator l ike protein 1 (i.e., BMAL1) is intimately associated with S-adenosylhomocysteine hydrolase (SAHH) and Hcy metabolism but how trans-sulfuration pathway is influenced by the circadian clock system remains unexplored. We hypothesize that potential alterations in the functioning of circadian clock during sleep and wake cycle affect the skeletal muscle’s biology. To test this hypothesis, we measured serum matrix metalloproteinases (MMPs) activities using gelatin gels for analyzing the MMP-2 and MMP-9 activities. Further, employing the casein gels we also studied MMP-13 that is known to be influenced by the growth arrest and DNA damage-45 (GADD45) protein during sleep and wake cycle. The wild type (WT) and cystathionine β synthase deficient (CBS-/+) mice strains were treated with H2S and subjected for measurement of trans-sulfuration factors from their skeletal muscle tissues. The results suggested highly robust activation of MMPs activities in the wake mice versus sleep mice that appears somewhat akin to that of the “ 1-carbon metabolic dysregulation” which takes place during remodeling of extracellular matrix (ECM) in muscular dystrophy affected tissues. Interestingly, the levels of trans-sulphuration factors such as CBS, cystathionine γ lyase (CSE), methyl tetrahydrofolate reductase (MTHFR), phosphatidylethanolamine N-methyltransferase (PEMT), and Hcy-protein bound paraoxonase 1 (PON1) were attenuated in the CBS-/+ mice. However, treatment with H2S mitigated the attenuation occurring in the trans-sulfuration pathway. In addition, levels of mitochondrial peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC 1-α) and mitofusin-2 (MFN-2) were significantly improved by H2S intervention. Our findings suggest participation of the circadian clock system in trans-sulfuration pathway that affect the skeletal muscle remodeling and mitochondrial regeneration. HL-139047, DK116591 and AR-71789 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.