A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle.
A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle.
复制标题
线粒体融合蛋白 2/HIF1α 轴在骨骼肌再生过程中设置了成熟检查点。
DOI：
10.1172/jci161638
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发表时间：
2022-12-01
影响因子：
15.9
通讯作者：
Mishra, Prashant
中科院分区：
文献类型：
--
作者：
Wang, Xun;Jia, Yuemeng;Zhao, Jiawei;Lesner, Nicholas P.;Menezes, Cameron J.;Shelton, Spencer D.;Venigalla, Siva Sai Krishna;Xu, Jian;Cai, Chunyu;Mishra, Prashant
再生医学的一个基本问题是是否存在限制修复过程速度和效率的内源性调节机制。我们报告了肌肉再生过程中存在一个成熟检查点，在新生儿阶段暂停肌纤维。该检查点由线粒体蛋白质线粒体融合蛋白2（Mfn 2）调节，其表达响应于肌肉损伤而被激活。Mfn 2是再生肌纤维生长和成熟所必需的;在Mfn 2缺乏的情况下，新的肌纤维在新生期停滞，其特征在于中央成核肌纤维和新生肌球蛋白重链基因处H3 K27 me 3抑制标记的缺失。在人类中枢性肌病的婴儿病例中观察到了新生儿阶段的类似停滞。从机制上讲，Mfn 2上调抑制了缺氧诱导因子1α（HIF 1 α）的表达，该因子是在肌肉损伤的情况下诱导的。持续的HIF 1 α信号传导阻断了从胚胎到成年的命运转变中新肌纤维的成熟，揭示了延迟肌肉再生的检查点的存在。相应地，抑制HIF 1 α可以使肌纤维绕过检查点，从而加速修复过程。我们得出结论，骨骼肌含有再生检查点，调节肌纤维成熟的速度，以响应Mfn 2和HIF 1 α活性。
A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration that pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), the expression of which is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of hypoxia-induced factor 1α (HIF1α), which is induced in the setting of muscle damage. Sustained HIF1α signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of HIF1α allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint that regulates the speed of myofiber maturation in response to Mfn2 and HIF1α activity.