The emerging role of Piezo1 channels in skeletal muscle physiology

Abstract

Piezo1 channels are mechanically activated (MA) cation channels that are involved in sensing of various mechanical perturbations, such as membrane stretch and shear stress, and play a crucial role in cell mechanotransduction. In response to mechanical stimuli, these channels open up and allow cations to travel into the cell and induce biochemical reactions that can change the cell's metabolism and function. Skeletal muscle cells/fibers inherently depend upon mechanical cues in the form of fluid shear stress and contractions (physical exercise). For example, an exposure of skeletal muscles to chronic mechanical loading leads to increased anabolism and fiber hypertrophy, while prolonged mechanical unloading results in muscle atrophy. MA Piezo1 channels have recently emerged as key mechanosensors that are capable of linking mechanical signals and intramuscular signaling in skeletal muscle cells/fibers. This review will summarize the emerging role of Piezo1 channels in the development and regeneration of skeletal muscle tissue as well as in the regulation of skeletal muscle atrophy. In addition, an overview of potential Piezo1-related signaling pathways underlying anabolic and catabolic processes will be provided. A better understanding of Piezo1's role in skeletal muscle mechanotransduction may represent an important basis for the development of therapeutic strategies for maintaining muscle functions under disuse conditions and in some disease states.

Keywords: Intracellular signaling; Mechanotransduction; Myogenesis; Piezo1; Skeletal muscle.

Fig. 1

A diagram showing the central pore module and the peripheral mechanotransduction module of the Piezo1 channel. Modified from Ge et al. (2015), Saotome et al. (2018), and Qin et al. (2021). The pore module consists of the extracellular Cap structure, the transmembrane pore, and the intracellular C-terminal domain (CTD), while the mechanotransduction module contains beam-like structures, peripheral blades, and anchor domains

Fig. 2

A diagram showing the key modulators of Piezo1 activity

Fig. 3

A diagram demonstrating the effect of Piezo-1 activation on postnatal myogenesis (Bosutti et al. 2021)

Fig. 4

A diagram showing the involvement of Piezo1-dependent signaling in skeletal muscle atrophy induced by cast immobilization. The diagram is based on the study by Hirata et al. (2022). KLF15: Krüppel-like factor 15; IL-6: interleukin-6; STAT3: signal transducer and activator of transcription 3

Fig. 5

Plausible Piezo1-dependent signaling pathways in skeletal muscle fibers. CaM: Ca²⁺-calmodulin; CaMK: Ca²⁺-calmodulin-dependent protein kinase; JNK: c-jun N-terminal kinase; p70S6K: ribosomal protein S6 kinase; mTORC1: mechanistic target of rapamycin complex 1; NOS: nitric oxide synthase; NO: nitric oxide; GSK-3: glycogen synthase kinase 3; eIF2B: eukaryotic translation initiation factor 2B; c-Myc: myelocytomatosis oncogene; Myh7: myosin heavy chain 7; NFAT: nuclear factor of activated T-cells, YAP: yes-associated protein; RhoA: Ras homolog family member A; ROCK: Rho-associated coiled-coil-containing protein kinase 1; ?: a link between Ca²⁺ and mechanically induced mTORC1 activation is contentious