Regulation of myonuclear positioning and muscle function by the skeletal muscle-specific CIP protein
Regulation of myonuclear positioning and muscle function by the skeletal muscle-specific CIP protein
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骨骼肌特异性 CIP 蛋白对肌核定位和肌肉功能的调节
DOI：
10.1073/pnas.1922911117
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发表时间：
2020-08-11
影响因子：
11.1
通讯作者：
Wang, Da-Zhi
中科院分区：
文献类型：
--
作者：
Liu, Jianming;Huang, Zhan-Peng;Wang, Da-Zhi
骨骼肌肌纤维内肌核的适当排列对于正常的肌肉功能至关重要，并且不适当的肌纤维定位与多种骨骼肌疾病有关，例如中枢性肌病和肌营养不良症。然而，控制肌球蛋白定位的分子仍然难以捉摸。在这里，我们报告，骨骼肌特异性CIP（SK-CIP）是一个调节器的核定位。小鼠中sk-CIP的遗传缺失导致肌核沿着肌纤维和在体内的特化结构如神经肌肉接头（NMJ）和肌腱接头（MT.Is）处的不对准，损害肌肉再生后的肌纤维定位，导致mdx小鼠（杜氏肌营养不良的小鼠模型）中的严重肌营养不良。sk-CIP定位于成肌细胞的中心体，并在分化时重新定位于肌管的外核包膜。从机制上讲，我们发现sk-CIP与核骨架和细胞骨架（LINC）复合物的接头和中心粒微管组织中心（MTOC）蛋白相互作用，以协调调节myc定位和对齐。这些结果表明，sk-CIP可能作为肌肉特异性锚定蛋白，以调节核的位置在多核肌细胞。
The appropriate arrangement of myonuclei within skeletal muscle myofibers is of critical importance for normal muscle function, and improper myonuclear localization has been linked to a variety of skeletal muscle diseases, such as centronuclear myopathy and muscular dystrophies. However, the molecules that govern myonuclear positioning remain elusive. Here, we report that skeletal muscle-specific CIP (sk-CIP) is a regulator of nuclear positioning. Genetic deletion of sk-CIP in mice results in misalignment of myonuclei along the myofibers and at specialized structures such as neuromuscular junctions (NMJs) and myotendinous junctions (MT.Is) in vivo, impairing myonuclear positioning after muscle regeneration, leading to severe muscle dystrophy in mdx mice, a mouse model of Duchenne muscular dystrophy. sk-CIP is localized to the centrosome in myoblasts and relocates to the outer nuclear envelope in myotubes upon differentiation. Mechanistically, we found that sk-CIP interacts with the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the centriole Microtubule Organizing Center (MTOC) proteins to coordinately modulate myonuclear positioning and alignment. These findings indicate that sk-CIP may function as a muscle-specific anchoring protein to regulate nuclear position in multinucleated muscle cells.