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线粒体相关膜与 Notch 信号在骨骼肌萎缩中的相互调节作用。

The reciprocal regulation between mitochondrial-associated membranes and Notch signaling in skeletal muscle atrophy.

机构信息

Faculty of Medical Sciences, Fujita Health University, Toyoake, Japan.

Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.

出版信息

Elife. 2023 Dec 15;12:RP89381. doi: 10.7554/eLife.89381.

DOI:10.7554/eLife.89381
PMID:38099641
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10723794/
Abstract

Skeletal muscle atrophy and the inhibition of muscle regeneration are known to occur as a natural consequence of aging, yet the underlying mechanisms that lead to these processes in atrophic myofibers remain largely unclear. Our research has revealed that the maintenance of proper mitochondrial-associated endoplasmic reticulum membranes (MAM) is vital for preventing skeletal muscle atrophy in microgravity environments. We discovered that the deletion of the mitochondrial fusion protein Mitofusin2 (MFN2), which serves as a tether for MAM, in human induced pluripotent stem (iPS) cells or the reduction of MAM in differentiated myotubes caused by microgravity interfered with myogenic differentiation process and an increased susceptibility to muscle atrophy, as well as the activation of the Notch signaling pathway. The atrophic phenotype of differentiated myotubes in microgravity and the regenerative capacity of Mfn2-deficient muscle stem cells in dystrophic mice were both ameliorated by treatment with the gamma-secretase inhibitor DAPT. Our findings demonstrate how the orchestration of mitochondrial morphology in differentiated myotubes and regenerating muscle stem cells plays a crucial role in regulating Notch signaling through the interaction of MAM.

摘要

骨骼肌萎缩和肌肉再生抑制是衰老的自然结果，但导致萎缩肌纤维发生这些过程的潜在机制在很大程度上仍不清楚。我们的研究表明，维持适当的线粒体相关内质网膜（MAM）对于防止微重力环境下的骨骼肌萎缩至关重要。我们发现，缺失线粒体融合蛋白 Mitofusin2（MFN2），它作为 MAM 的连接物，在人诱导多能干细胞（iPS）或微重力引起的分化肌管中 MAM 的减少，会干扰成肌分化过程，增加肌肉萎缩的易感性，并激活 Notch 信号通路。微重力下分化肌管的萎缩表型和营养不良小鼠中 Mfn2 缺陷的肌肉干细胞的再生能力都可以通过用γ-分泌酶抑制剂 DAPT 治疗得到改善。我们的研究结果表明，分化肌管和再生肌肉干细胞中线粒体形态的协调如何通过 MAM 的相互作用在调节 Notch 信号中发挥关键作用。

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