Satellite cell-specific deletion of Cipc alleviates myopathy in mdx mice

Skeletal muscle regeneration relies on satellite cells that can proliferate, differentiate, and form new myofibers upon injury. Emerging evidence suggests that misregulation of satellite cell fate and function influences the severity of Duchenne muscular dystrophy (DMD). The transcription factor Pax7 determines the myogenic identity and maintenance of the pool of satellite cells. The circadian clock regulates satellite cell proliferation and self-renewal. Here, we show that the CLOCK-interacting protein Circadian (CIPC) a negative-feedback regulator of the circadian clock, is up-regulated during myoblast differentiation. Specific deletion of Cipc in satellite cells alleviates myopathy, improves muscle function, and reduces fibrosis in mdx mice. Cipc deficiency leads to activation of the ERK1/2 and JNK1/2 signaling pathways, which activates the transcription factor SP1 to trigger the transcription of Pax7 and MyoD. Therefore, CIPC is a negative regulator of satellite cell function, and loss of Cipc in satellite cells promotes muscle regeneration. [Display omitted] •CIPC is up-regulated during myoblast differentiation•Specific deletion of Cipc in satellite cells alleviates myopathy in mdx mice•Cipc deficiency leads to activation of SP1 to trigger the transcription of Pax7•Loss of Cipc in satellite cells promotes muscle regeneration Zheng et al. demonstrate that myopathy in mdx mice can be alleviated by deleting Cipc in satellite cells. CIPC is an inhibitor of Pax7 expression. Deleting Cipc in satellite cells activates ERK1/2 and JNK1/2 signaling pathways, leading to phosphorylation of SP1, which augments the gene expression of Pax7.