HOIL-1L deficiency was recently reported to be one of the causes of myopathy and dilated cardiomyopathy (DCM). However, the mechanisms by which myopathy and DCM develop have not been clearly elucidated. Here, we sought to elucidate these mechanisms using the murine myoblast cell line C2C12 and disease-specific human induced pluripotent stem cells (hiPSCs). Myotubes differentiated from HOIL-1L-KO C2C12 cells exhibited deteriorated differentiation and mitotic cell accumulation. CMs differentiated from patient-derived hiPSCs had an abnormal morphology with a larger size and were excessively multinucleated compared with CMs differentiated from control hiPSCs. Further analysis of hiPSC-derived CMs showed that HOIL-1L deficiency caused cell cycle alteration and mitotic cell accumulation. These results demonstrate that abnormal cell maturation possibly contribute to the development of myopathy and DCM. In conclusion, HOIL-1L is an important intrinsic regulator of cell cycle-related myotube and CM maturation and cell proliferation.

最近报道 HOIL-1L 缺陷是肌病和扩张型心肌病 (DCM) 的原因之一。然而，肌病和扩张型心肌病发生的机制尚未明确阐明。在这里，我们试图利用鼠成肌细胞系 C2C12 和疾病特异性人类诱导多能干细胞 (hiPSC) 来阐明这些机制。从 HOIL-1L-KO C2C12 细胞分化的肌管表现出分化恶化和有丝分裂细胞积累。与从对照 hiPSC 分化的 CM 相比，从患者来源的 hiPSC 分化的 CM 具有较大尺寸的异常形态，并且过度多核。对 hiPSC 衍生的 CM 的进一步分析表明 HOIL-1L 缺陷导致细胞周期改变和有丝分裂细胞积累。这些结果表明细胞成熟异常可能导致肌病和 DCM 的发生。总之，HOIL-1L 是细胞周期相关肌管和 CM 成熟和细胞增殖的重要内在调节因子。