Deletion of Cipc promotes regenerative myogenesis in mdx mice and is associated with increased myogenin expression.

Skeletal muscle regeneration depends on satellite cells, which proliferate, differentiate, and fuse to repair damaged myofibers. Satellite-cell dysfunction contributes to defective regeneration in Duchenne muscular dystrophy (DMD), but the contribution of circadian regulators to this process remains incompletely understood. Here, we investigated the role of the CLOCK-interacting protein CIPC in satellite-cell differentiation and muscle regeneration in mdx mice. Satellite cell-specific deletion of Cipc increased centrally nucleated fibers and embryonic myosin heavy chain-positive regenerating fibers in dystrophic and ischemia-reperfusion-injured tibialis anterior muscles, and enhanced MyHC-positive myotube formation in primary cultures. Cipc deletion was accompanied by increased MyoD and myogenin mRNA expression and a higher number of myogenin-positive cells. RNA sequencing of day-3 differentiated satellite cells identified Mapk14/p38α and Elk1 as candidate upstream regulators associated with increased myogenin expression. Immunoblotting in three independent experiments further showed increased p38 and ELK-1 phosphorylation in Cipc-deficient satellite cells, without an apparent genotype-dependent change in total p38 or total ELK-1 abundance. These findings indicate that Cipc deletion enhances regenerative myogenesis in mdx mice and is associated with increased p38/ELK-1 signaling and myogenin expression. Because pathway inhibition, ELK-1 promoter-occupancy, and myogenin loss-of-function experiments were not performed, the p38/ELK-1-myogenin axis should be regarded as a candidate mechanism rather than an established causal pathway.