Triolo Matthew, Baker Nicole, Agarwal Soniya, Larionov Nikita, Podinić Tina, Khacho Mireille
Department of Biochemistry, Microbiology and Immunology, Center for Neuromuscular Disease (CNMD), Ottawa Institute of Systems Biology (OISB), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
iScience. 2024 Feb 9;27(3):109164. doi: 10.1016/j.isci.2024.109164. eCollection 2024 Mar 15.
Myogenic differentiation is integral for the regeneration of skeletal muscle following tissue damage. Though high-energy post-mitotic muscle relies predominantly on mitochondrial respiration, the importance of mitochondrial remodeling in enabling muscle differentiation and the players involved are not fully known. Here we show that the mitochondrial fusion protein OPA1 is essential for muscle differentiation. Our study demonstrates that OPA1 loss or inhibition, through genetic and pharmacological means, abolishes muscle regeneration and myotube formation. We show that both the inhibition and genetic deletion of OPA1 prevent the early onset metabolic switch required to drive myoblast differentiation. In addition, we observe an OPA1-dependent upregulation of the supercomplex assembly factor, SCAF1, at the onset of differentiation. Importantly, preventing the upregulation of SCAF1, through OPA1 loss or siRNA-mediated SCAF1 knockdown, impairs metabolic reprogramming and muscle differentiation. These findings reveal the integral role of OPA1 and mitochondrial reprogramming at the onset of myogenic differentiation.
生肌分化对于组织损伤后骨骼肌的再生至关重要。尽管处于有丝分裂后阶段的高能肌肉主要依赖线粒体呼吸作用，但线粒体重塑在促进肌肉分化中的重要性以及相关参与因素尚未完全明确。在此，我们表明线粒体融合蛋白OPA1对肌肉分化至关重要。我们的研究表明，通过基因和药理学手段使OPA1缺失或受到抑制，会消除肌肉再生和肌管形成。我们发现，OPA1的抑制和基因缺失均会阻止驱动成肌细胞分化所需的早期代谢转换。此外，我们观察到在分化开始时，超复合体组装因子SCAF1存在OPA1依赖性上调。重要的是，通过OPA1缺失或小干扰RNA介导的SCAF1敲低来阻止SCAF1的上调，会损害代谢重编程和肌肉分化。这些发现揭示了OPA1和线粒体重编程在生肌分化开始时的不可或缺作用。
