Circadian timing-dependent myoblast differentiation and muscle regeneration

Circadian rhythms regulate cell proliferation and differentiation but circadian control of tissue regeneration remains elusive at the molecular level. Here, we show that the circadian master regulators Per1 and Per2 are integral components defining the efficiency of myoblast differentiation and muscle regeneration. We found that the depletion of Per1 or Per2 suppressed myoblast differentiation and muscle regeneration , demonstrating their non-redundant functions. Both Per1 and Per2 directly activated Igf2, an autocrine promoter of myoblast differentiation, accompanied by Per-dependent recruitment of RNA polymerase II, dynamic histone modifications at the promoter and enhancer, and the promoter-enhancer interaction. This circadian epigenetic oscillation created a preferred time window for initiating myoblast differentiation. Consistently, muscle regeneration was faster if initiated at night when Per1, Per2, and Igf2 were highly expressed compared with morning. This study reveals the circadian timing as a significant factor for effective muscle cell differentiation and regeneration.