Adult muscle satellite cells (MuSCs) are quiescent in uninjured homeostatic muscles. Upon muscle injury, MuSCs exit quiescence, re-enter the cell cycle and self-renew, then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Previously, our laboratory demonstrated that Pax3 and Pax7 binding protein 1 (Paxbp1) interacts with Pax7 and is required for the induction of Pax7 target genes in proliferative muscle precursor cells in juvenile mice. However, the roles of Paxbp1 in adult MuSCs remain unknown. Here, we report that Paxbp1 controls a key activation checkpoint during MuSC quiescence exit and is indispensable for MuSC-mediated muscle regeneration. Deletion of Paxbp7 in adult MuSCs prevente...[ Read more ]

Adult muscle satellite cells (MuSCs) are quiescent in uninjured homeostatic muscles. Upon muscle injury, MuSCs exit quiescence, re-enter the cell cycle and self-renew, then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Previously, our laboratory demonstrated that Pax3 and Pax7 binding protein 1 (Paxbp1) interacts with Pax7 and is required for the induction of Pax7 target genes in proliferative muscle precursor cells in juvenile mice. However, the roles of Paxbp1 in adult MuSCs remain unknown. Here, we report that Paxbp1 controls a key activation checkpoint during MuSC quiescence exit and is indispensable for MuSC-mediated muscle regeneration. Deletion of Paxbp7 in adult MuSCs prevented them from re-entering the cell cycle upon injury resulting in a total regeneration failure. Unlike Pax7, Paxbp1 is not required for the maintenance of quiescent MuSCs (QSCs). While the initial phase of early activation is relatively normal in Paxbp1-null MuSCs, the subsequent phase of rapid cell growth and metabolic reprogramming was severely impaired. Mechanistically, we found an abnormal elevation of reactive oxygen species (ROS) in Paxbp1-null MuSCs, which induced p53 activation and impaired mTORC1 signaling leading to defective cell growth, apoptosis, and failure in S-phase re-entry. Deliberate ROS reduction partially rescued the cell cycle re-entry defect in mutant MuSCs. Our study reveals that Paxbp1 regulates a late cell growth checkpoint essential for QSCs to re-enter the cell cycle upon activation and uncovers a Pax7-independent function of Paxbp1.