Mechano-signaling via Piezo1 prevents activation and p53-mediated senescence of muscle stem cells
Yundong Peng,
Jingjing Du,
Stefan Günther,
Xinyue Guo,
Shengpeng Wang,
Andre Schneider,
Li Zhu,
Thomas Braun
Affiliations
Yundong Peng
Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231, Bad Nauheim, Germany
Jingjing Du
Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231, Bad Nauheim, Germany; College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China
Stefan Günther
Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231, Bad Nauheim, Germany
Xinyue Guo
Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231, Bad Nauheim, Germany
Shengpeng Wang
Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, No.76 West Yanta Road, Yanta District, Xi'an, China
Andre Schneider
Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231, Bad Nauheim, Germany
Li Zhu
College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Corresponding author.
Thomas Braun
Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231, Bad Nauheim, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt am Main, Germany; Corresponding author. Dept. of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstr. 43, Germany..
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.
