Abstract
Skeletal muscle stem cells (MuSC), also called satellite cells, are indispensable for maintenance and regeneration of adult skeletal muscles. Yet, a comprehensive picture of the regulatory events controlling the fate of MuSC is missing. Here, we determine the proteome of MuSC to design a loss-of-function screen, and identify 120 genes important for MuSC function including the arginine methyltransferase Prmt5. MuSC-specific inactivation of Prmt5 in adult mice prevents expansion of MuSC, abolishes long-term MuSC maintenance and abrogates skeletal muscle regeneration. Interestingly, Prmt5 is dispensable for proliferation and differentiation of Pax7+ myogenic progenitor cells during mouse embryonic development, indicating significant differences between embryonic and adult myogenesis. Mechanistic studies reveal that Prmt5 controls proliferation of adult MuSC by direct epigenetic silencing of the cell cycle inhibitor p21. We reason that Prmt5 generates a poised state that keeps MuSC in a standby mode, thus allowing rapid MuSC amplification under disease conditions.
Highlights
Skeletal muscle stem cells (MuSC), called satellite cells, are indispensable for maintenance and regeneration of adult skeletal muscles
Protein extracts of freshly isolated MuSCs were subjected to mass spectrometry analysis (n 1⁄4 3) resulting in the identification of 135,341 peptides in all samples combined corresponding to 5,031 proteins in MuSC with at least one unique peptide (Supplementary Data 1)
Comparison with proteome data sets obtained from myofibres, Pax7- mononuclear cells and the MuSCPG fraction allowed us to identify 441 proteins that are exclusively present in MuSC but not in differentiated myofibres (Fig. 1a and Supplementary Data 2)
Summary
Skeletal muscle stem cells (MuSC), called satellite cells, are indispensable for maintenance and regeneration of adult skeletal muscles. Adult skeletal muscle stem cells (MuSC) are represented by a specialized subset of myofibre-associated cells called satellite cells and own a remarkable regenerative potential, which enables them to continuously replace myofibres by undergoing repeated rounds of activation and expansion under persisting disease conditions. The molecular mechanisms that control satellite cell functions during skeletal muscle regeneration are only partially understood, several factors directing the fate of MuSC have been identified (reviewed in refs 2,11). We find that Prmt[5] is essential for adult MuSC proliferation and muscle regeneration by restricting p21 expression via direct epigenetic silencing, thereby allowing rapid expansion of MuSC. Since the lack of Prmt[5] does not affect embryonic myogenesis, we postulate that prenatal muscle development and adult muscle regeneration use distinct genetic and epigenetic mechanisms for the control of muscle progenitor cell expansion
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