PDF(Pubmed)
Abstract：
As the largest organ in the human body, skeletal muscle is essential for breathing support, movement initiation, and maintenance homeostasis. It has been shown that programmed cell death (PCD), which includes autophagy, apoptosis, and necrosis, is essential for the development of skeletal muscle. A novel form of PCD called ferroptosis is still poorly understood in relation to skeletal muscle. In this study, we observed that the activation of ferroptosis significantly impeded the differentiation of C2C12 myoblasts into myotubes and concurrently suppressed the expression of OTUB1, a crucial deubiquitinating enzyme. OTUB1-silenced C2C12 mouse myoblasts were used to investigate the function of OTUB1 in ferroptosis. The results show that OTUB1 knockdown in vitro significantly increased C2C12 ferroptosis and inhibited myogenesis. Interestingly, the induction of ferroptosis resulting from OTUB1 knockdown was concomitant with the activation of autophagy. Furthermore, OTUB1 interacted with the P62 protein and stabilized its expression by deubiquitinating it, thereby inhibiting autophagy-dependent ferroptosis and promoting myogenesis. All of these findings demonstrate the critical role that OTUB1 plays in controlling ferroptosis, and we suggest that focusing on the OTUB1-P62 axis may be a useful tactic in the treatment and prevention of disorders involving the skeletal muscle.
摘要：
作为人体最大的器官，骨骼肌是呼吸支持所必需的,运动启动,和维持体内平衡。已经表明，程序性细胞死亡(PCD)其中包括自噬，凋亡，和坏死，对骨骼肌的发育至关重要。关于骨骼肌，一种称为铁中毒的PCD的新形式仍然知之甚少。在这项研究中,我们观察到，铁凋亡的激活显着阻碍了C2C12成肌细胞分化为肌管，同时抑制了关键的去泛素化酶OTUB1的表达。使用OTUB1沉默的C2C12小鼠成肌细胞来研究OTUB1在铁凋亡中的功能。结果表明，体外OTUB1敲低可显著增加C2C12的铁细胞凋亡，抑制肌生成。有趣的是,由OTUB1敲除引起的铁凋亡的诱导伴随着自噬的激活。此外，OTUB1与P62蛋白相互作用，并通过去泛素化来稳定其表达，从而抑制自噬依赖性铁凋亡并促进肌生成。所有这些发现都证明了OTUB1在控制铁凋亡中的关键作用，我们建议关注OTUB1-P62轴可能是治疗和预防涉及骨骼肌疾病的有用策略。
