Mechano-signaling via Piezo1 prevents activation and p53-mediated senescence of muscle stem cells

Skeletal muscle stem cells (MuSCs), also called satellite cells, are instrumental for postnatal muscle growth and skeletal muscle regeneration. Numerous signaling cascades regulate the fate of MuSCs during muscle regeneration but the molecular mechanism by which MuSCs sense mechanical stimuli remain unclear. Here, we describe that Piezo1, a mechanosensitive ion channel, keeps MuSCs in a quiescent state and prevents senescence. Absence of Piezo1 induces precocious activation of MuSCs, attenuates proliferation, and impairs differentiation, essentially abolishing efficient skeletal muscle regeneration and replenishment of the MuSC pool. Furthermore, we discovered that inactivation of Piezo1 results in compensatory up-regulation of T-type voltage-gated Ca2+ channels, leading to increased Ca-2+ influx, which strongly induces NOX4 expression via cPKC. Elevated NOX4 expression in Piezo1-deficient MuSCs increases ROS levels and DNA damage, causing P53-dependent cellular senescence and cell death. The importance of the P53/P21-axis for mediating Piezo1-dependent cellular defects was confirmed by pharmacological inhibition of P53 in Piezo1-deficient mice, which abrogates increased senescence of muscle cells and normalizes muscle regeneration. Our findings uncover an essential role of Piezo1mediated mechano-signaling in MuSCs for maintaining quiescence and preventing senescence. Reduced mechano-signaling due to decreased physical activity during aging may contribute to the increase of senescent cells and the decline of MuSC numbers in geriatric mice and humans.

Automated summary

Skeletal muscle stem cells, also known as satellite cells, play a crucial role in postnatal muscle growth and regeneration. This study reveals that Piezo1, a mechanosensitive ion channel, is essential for maintaining the quiescence and preventing senescence of muscle stem cells. Absence of Piezo1 leads to premature activation of these cells, impairs their proliferation and differentiation, and significantly hinders skeletal muscle regeneration. The inactivation of Piezo1 results in compensatory up-regulation of T-type voltage-gated Ca2+ channels, which increases the influx of Ca2+ and induces NOX4 expression through cPKC. The elevated expression of NOX4 in Piezo1-deficient cells leads to increased levels of reactive oxygen species (ROS) and DNA damage, causing P53-dependent cellular senescence and cell death. The study also highlights the importance of the P53/P21-axis in mediating the cellular defects caused by the absence of Piezo1. This research sheds light on the critical role of Piezo1-mediated mechano-signaling in maintaining the quiescence and preventing senescence of muscle stem cells, and suggests that reduced mechano-signaling during aging may contribute to the accumulation of senescent cells and the decline of muscle stem cell numbers in geriatric individuals.