The GPCR-G12/13-RhoA signaling axis: a key player in the regulation of MuSC quiescence

Abstract

Adult skeletal muscle stem cells (MuSCs) predominantly rest in a quiescent state during homeostasis, which enables long-term survival and preserves self-renewal capacity. MuSCs respond promptly to environmental cues, ultimately contributing to the maintenance and regeneration of skeletal muscles throughout an individual's lifespan. Over the past few decades, there has been a surge in scientific interest to unravel the intricate physiological properties and molecular foundations governing the quiescence of muscle stem cells (MuSCs). Despite valuable insights from previous investigations, fundamental questions remain. The molecular mechanisms orchestrating the intrinsic regulatory network of MuSCs, fortifying their quiescent state, are still incompletely understood. G-protein-coupled receptors (GPCRs) have emerged as one of the important regulators for mantaining MuSC quiescence. However, the specific repertoire of GPCRs residing within quiescent MuSCs, as well as the regulatory circuitry governing their activity, remain largely unexplored. In this study, I comprehensively characterized the expression and function of GPCR within quiescent MuSCs. I used a multidimensional approach, encompassing pharmacological interventions and inducible-genetic strategies, resulting in the identification of critical G-proteins and two GPCR ligands, endothelin-3 (ET-3) and neurotensin (NT). These ligands, partially derived from the MuSC niche selectively engage EDNRB and NTSR2 receptors, respectively, thereby activating the G12/13 signaling pathway in MuSCs. I discovered that this signaling cascade is critical to maintain MuSC quiescence by regulating the activity of RhoA. Collectively, my findings unravel the intricate network of GPCR signaling pathways governing MuSC quiescence, illuminating the pivotal role played by the "GPCRs-G12/13-RhoA" axis in preserving the quiescent state of MuSCs. Notably, this novel discovery bears therapeutic potential for improving functionality of MuSC, which will help to treat myopathies.