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bioRxiv · 10.1101/2023.05.17.541238

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

Madigan, L. A.·Jaime, D.·Fallon, J. R.
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Abstract

A central question in adult stem cell biology is elucidating the signaling pathways regulating their dynamics and function in diverse physiological and age-related contexts. Muscle stem cells in adults (Satellite Cells; SCs) are generally quiescent but can activate and contribute to muscle repair and growth. Here we tested the role of the MuSK-BMP pathway in regulating adult SC quiescence by deletion of the BMP-binding MuSK Ig3 domain ( {Delta}Ig3-MuSK). At 3 months of age SC and myonuclei numbers and myofiber size were comparable to WT. However, at 5 months of age 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. Transcriptomic analysis showed that SCs from uninjured {Delta}Ig3-MuSK mice exhibit signatures of activation. Regeneration experiments showed that {Delta}Ig3-MuSK SCs maintain full stem cell function. Expression of {Delta}Ig3-MuSK in adult SCs was sufficient to break quiescence and increase myofiber size. 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. HighlightsO_LIMuSK, in its role as a BMP co-receptor, regulates adult muscle stem cell quiescence C_LIO_LIThe MuSK-BMP pathway acts cell autonomously C_LIO_LIIncreased muscle size and function with preservation of myonuclear density and stemness in mice with attenuated MuSK-BMP signaling C_LI

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Madigan, L. A., Jaime, D., Fallon, J. R.. 2023-05-18. MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size. https://doi.org/10.1101/2023.05.17.541238

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