Concerted Molecular Clock Control of Myogenic Precursor Properties Promotes Skeletal Muscle Growth and Remodeling

Abstract

Circadian clock imparts temporal regulation on diverse physiological processes. We and others recently demonstrated that the clock circuit plays an important role in muscle growth and repair for maintenance of muscle mass, raising the possibility of targeting this machinery for muscle‐wasting disease therapies. Currently, the mechanisms underlying clock regulation of muscle growth processes are largely unknown. Here we show that the antagonistic actions of the essential clock transcriptional activator, Brain and Muscle Ant‐like 1 (Bmal1), and the clock repressor protein, Rev‐erbα, coordinately modulate myogenic precursor cell (MPC) differentiation and proliferation properties to facilitate muscle growth and remodeling. We were the first to report a novel function of Bmal1 in promoting MPC myogenic differentiation required for skeletal muscle regenerative repair. Current studies reveal that the clock transcription repressor Rev‐erbα suppresses myocyte development and its genetic loss of function promotes regenerative myogenesis, through its negative transcription control of target genes in the Wnt signaling pathway. Furthermore, we show that Bmal1 promotes, whereas Reverbα inhibits MPC proliferative behavior in vitro and upon muscle regeneration, mediated by their respective transcriptional regulations of cell cycle regulators. Notably, our work uncovers that mechanical stretch and exercise‐associated signals induce clock gene expression, suggesting their roles in entraining the cell‐autonomous muscle clock oscillators to physiological stimuli. Collectively, our studies reveal concerted functions of the muscle‐resident clock machinery in orchestrating MPC properties to contribute to muscle growth and consequently mass maintenance in accordance with myogenic cues. Elucidation of this temporal control in skeletal muscle tissue remodeling may offer novel therapeutic strategies to combat muscle‐wasting associated with aging, cancer or chronic diseases.Support or Funding InformationThis project is supported by grants American Heart Association 17GRNT33370012, Muscular Dystrophy Association 381294, and NIH DK 1R01DK112794 to KM.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.