MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

Abstract

ABSTRACTA central question in the biology of adult stem cells is elucidating the signaling pathways regulating their dynamics and function in diverse physiological and age-related contexts. Adult muscle stem cells (Satellite Cells; SCs) are generally quiescent but can activate and contribute to muscle homeostasis and repair. Here we tested the role of the MuSK-BMP pathway in regulating adult SC quiescence and myofiber size. We attenuated MuSK-BMP signaling by deletion of the BMP-binding MuSK Ig3 domain (‘ΔIg3-MuSK’) and studied the fast TA and EDL muscles. In germ line mutants at 3 months of age SC and myonuclei numbers as well as myofiber size were comparable in ΔIg3-MuSK and WT animals. However, in 5-month-old ΔIg3-MuSK animals SC density was decreased while myofiber size, myonuclear number and grip strength were increased - indicating that SCs had activated and productively fused into the myofibers over this interval. Notably, myonuclear domain size was conserved. Following injury, the mutant muscle fully regenerated with restoration of myofiber size and SC pool to WT levels, indicating that ΔIg3-MuSK SCs maintain full stem cell function. Conditional expression of ΔIg3-MuSK in adult SCs showed that the MuSK-BMP pathway regulates quiescence and myofiber size in a cell autonomous fashion. Transcriptomic analysis revealed that SCs from uninjured ΔIg3-MuSK mice exhibit signatures of activation, including elevated Notch and epigenetic signaling. We conclude that the MuSK-BMP pathway regulates SC quiescence and myofiber size in a cell autonomous, age-dependent manner. Targeting MuSK-BMP signaling in muscle stem cells thus emerges a therapeutic strategy for promoting muscle growth and function in the settings of injury, disease, and aging.