Muscle satellite cells (MuSCs), myogenic stem cells in skeletal muscles, play an essential role in muscle regeneration. After skeletal muscle injury, quiescent MuSCs are activated to enter the cell cycle and proliferate, thereby initiating regeneration; however, the mechanisms that ensure successful MuSC division, including chromosome segregation, remain unclear. Here, we show that PIEZO1, a calcium ion (Ca2+)-permeable cation channel activated by membrane tension, mediates spontaneous Ca2+influx to control the regenerative function of MuSCs. Our genetic engineering approach in mice revealed that PIEZO1 is functionally expressed in MuSCs and thatPiezo1deletion in these cells delays myofibre regeneration after injury. These results are, at least in part, due to a mitotic defect in MuSCs. Mechanistically, this phenotype is caused by impaired PIEZO1-Rho signalling during myogenesis. Thus, we provide the first concrete evidence that PIEZO1, a bona fide mechanosensitive ion channel, promotes proliferation and regenerative functions of MuSCs through precise control of cell division.

Muscle satellite cells (MuSCs), myogenic stem cells in skeletal muscle, play an essential role in muscle regeneration. During the regeneration process, cues from the surrounding microenvironment are critical for the proliferation and function of MuSCs. However, the mechanism by which mechanical stimuli from the MuSCs niche is converted into biochemical signals to promote muscle regeneration is yet to be determined. Here, we show that PIEZO1, a calcium ion (Ca2+)-permeable cation channel that is activated by membrane tension, mediates the spontaneous Ca2+ influx to controls the regenerative function of MuSCs. Our genetically engineering approach in mice revealed that PIEZO1 is functionally expressed in MuSCs, and the conditional deletion of Piezo1 in MuSCs delays myofiber regeneration after myofiber injury, which is at least in part due to the growth defect in MuSCs via the reduction in RhoA-mediated actomyosin formation. Thus, we provide the first evidence in MuSCs that PIEZO1, a bona fide mechanosensitive ion channel, promotes the proliferative and regenerative function during skeletal muscle regeneration.

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Muscle-resident stem cells called muscle satellite cells (MuSC) play an essential role in muscle regeneration. Mechanosensation is presumed to be critical for activation of MuSCs, but the molecular entity that determines the cell fate in MuSCs through converting the mechanical stimuli into biochemical signals remains to be elucidated. Here we identify PIEZO1, a mechanosensitive ion channel that is activated by membrane tension, as a critical determinant for activation of MuSCs. In silico analysis demonstrates that PIEZO1 is predominantly expressed in MuSCs but not in mature myofibers. By utilizing Piezo1-tdTomato mice where endogenous PIEZO1 is fused with a fluorescent protein tdTomato, our immunofluorescent analysis reveals that PIEZO1 is accumulated to the cleavage furrow during cell division of MuSCs. Moreover, a conditional deletion of Piezo1 leads to delayed myofibers regeneration after cardiotoxin-induced myofiber injury, at least in part due to the cell division delay in MuSCs. Thus, our results indicate that PIEZO1 is a bona fide mechanosensor whose ion channel activity is required for completion of cell division in MuSCs.