Satellite cell – specific deletion of CIPC alleviates myopathy in mdx mice.

The regeneration of skeletal muscle relies on satellite cells which can proliferate, differentiate and form new myofibers upon injury. Emerging evidence suggests that misregulations of satellite cell fate and function influence the severity of Duchenne Muscular Dystrophy (DMD). The myogenic identity and maintenance of the pool of satellite cells is determined by the transcription factor PAX7. Satellite cell proliferation and self-renewal is regulated by the circadian clock. 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 alleviated myopathy, improved muscle function and reduced fibrosis in mdx mice. CIPC deficiency led to activation of the ERK1/2 and JNK1/2 signaling pathways, which in turn activated the transcription factor SP1 to trigger the transcription of PAX7. Therefore, CIPC is a negative regulator of satellite cell function and loss of CIPC in satellite cells promotes muscle regeneration. Total RNA from Cipc+/+ and Cipc-/- satellite cells.