Elsevier

Redox Biology

Volume 52, June 2022, 102309
Redox Biology

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

https://doi.org/10.1016/j.redox.2022.102309Get rights and content
Under a Creative Commons license
open access

Highlights

  • Piezo1 is highly expressed in skeletal MuSCs and prevents their precocious activation.

  • Loss of Piezo1 increases Ca2+ influx into MuSCs, which induces NOX4 expression via PKC, leading to enhanced ROS generation.

  • Inactivation of Piezo1 depletes the MuSC pool and causes P53-dependent senescence of MuSCs.

  • ROS scavenging in Piezo1-deficient MuSCs prevents P53 accumulation.

  • Inhibition of P53 mitigates skeletal muscle regeneration defects in mice with Piezo1-deficient MuSCs.

Abstract

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 Ca2+ 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 Piezo1-mediated 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.

Keywords

Muscle stem cells
Mechanosensing
Senescence
p53
Skeletal muscle regeneration

Cited by (0)

1

Equal contribution.

2

Lead Contact.