Department of Integrative Physiology, School of Pharmaceutical Sciences,Abstract静岡県立大学薬学部統合生理学分野University of Shizuoka― 232 ―Skeletal muscle consists of numerous multinucleated cells known as myofibers that possess regenerative capacity in response to muscle damage. Muscle satellite cells (MuSCs), which are stem cells that reside on myofibers, play a fundamental role in muscle regeneration. MuSCs are thought to be activated by biophysical forces caused by changes in the microenvironmental niche, upon which they differentiate into myoblasts that fuse with each other to form new myofibers. However, the molecular mechanisms underlying muscle regeneration processes remain to be elucidated. For example, the manner by which mechanical stimuli are converted into biochemical signals in MuSCs for myofiber regeneration is unclear. In this study, we identified a series of ion channels including PIEZO1, a mechanosensitive Ca2+-permeable channel that is activated by membrane tension, as a key regulator of myofiber regeneration. Using Piezo1-tdTomato, a transgenic mouse line that expresses endogenous PIEZO1 fused with a fluorescent protein tdTomato at the C-terminus, we demonstrated that PIEZO1 accumulates in the midbody during MuSC division. Moreover, MuSC-specific deletion of Piezo1 resulted in impaired muscle regeneration following muscle injury, at least partly because of the abnormalities in cell division of undifferentiated MuSCs, such as the presence of chromosomal bridges and micronuclei, indicating that PIEZO1 plays a role in muscle regeneration by governing proper MuSC division in a Rho-dependent manner. In addition, during the course of this research, we also identified other mechanosensitive ion channels that is essential for a variety of cellular phenomenon as a key regulator of satellite cell functions. From these results, we have discovered that the permeation of cations such as Ca2+ through mechanosensitive channels acts as a molecular determinant for MuSCs activation that governs proper skeletal muscle regeneration.骨格筋幹細胞における細胞力覚機構の多様性とその意義Role of a diverse array of mechanosensitive ion channels in muscle satellite cells原 雄二Yuji Hara
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