Satellite cell – specific deletion of CIPC alleviates myopathy in mdx mice.. 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. Overall design: Total RNA from Cipc+/+ and Cipc-/- satellite cells.

骨骼肌再生依赖于卫星细胞 (satellite cells)——这类细胞可在机体损伤时增殖、分化并形成新生肌纤维 (myofibers)。越来越多的研究证据表明，卫星细胞命运与功能的异常调控会影响杜氏肌营养不良症 (Duchenne Muscular Dystrophy，DMD) 的病情严重程度。卫星细胞池的肌源性身份维持与稳态调控由转录因子PAX7决定。卫星细胞的增殖与自我更新过程受生物钟 (circadian clock) 调控。本研究发现，作为生物钟负反馈调节因子的CLOCK互作蛋白Circadian (CIPC)，在成肌细胞 (myoblast) 分化阶段表达上调。在mdx小鼠的卫星细胞中特异性敲除CIPC，可缓解肌病、改善肌肉功能并减轻组织纤维化程度。CIPC缺失会激活ERK1/2与JNK1/2信号通路，进而激活转录因子SP1，启动PAX7的转录。综上，CIPC是卫星细胞功能的负调控因子，卫星细胞中CIPC的缺失可促进骨骼肌再生。实验设计方案：取自Cipc+/+与Cipc-/-卫星细胞的总RNA (Total RNA)。