Paxbp1 controls a key checkpoint for cell growth and survival during early activation of quiescent muscle satellite cells

Abstract

Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon muscle injury, MuSCs exit quiescence, reenter the cell cycle to proliferate and self-renew, and then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Here, we report that Pax3 and Pax7 binding protein 1 (Paxbp1) controls a key checkpoint during this critical transition. Deletion of Paxbp1 in adult MuSCs prevented them from reentering the cell cycle upon injury, resulting in a total regeneration failure. 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 reentry. Deliberate ROS reduction partially rescued the cell-cycle reentry defect in mutant MuSCs. Our study reveals that Paxbp1 regulates a late cell-growth checkpoint essential for quiescent MuSCs to reenter the cell cycle upon activation.

A Long Journey before Cycling: Regulation of Quiescence Exit in Adult Muscle Satellite Cells

“…Another energy source used by quiescent MuSCs is autophagy, which is further boosted upon MuSC activation to meet the biosynthetic requirement by providing nutrients such as pyruvate [49,143]. Unlike FAOrelated transcripts, glycolysis-related transcripts are low in quiescent MuSCs but rapidly induced upon MuSC activation [128,144]. Although inefficient in producing ATP compared to OXPHOS, glycolysis provides essential metabolic intermediates for cell growth and biosynthesis that are, in turn, required for cell cycle re-entry.…”

“…Although required for MuSC early activation, glycolysis seems to be dispensable in proliferating myoblasts, where glucose is mainly used to maintain histone acetylation levels by providing acetyl-CoA [146]. Compared to activated MuSCs, both mitochondria numbers and activities are low in quiescent MuSCs [62,144,147]. Upregulation of OXPHOS upon MuSC activation also elicits a burst in ROS levels [147], the dysregulation of which could trigger cellular senescence or apoptosis [144,147,148].…”

“…Compared to activated MuSCs, both mitochondria numbers and activities are low in quiescent MuSCs [62,144,147]. Upregulation of OXPHOS upon MuSC activation also elicits a burst in ROS levels [147], the dysregulation of which could trigger cellular senescence or apoptosis [144,147,148]. Of note, blocking either glycolysis or electron transport chain activity in MuSCs strongly prevents quiescence exit and the subsequent cell cycle re-entry, highlighting the importance of metabolic reprogramming during early MuSC activation [140,144].…”

“…Upregulation of OXPHOS upon MuSC activation also elicits a burst in ROS levels [147], the dysregulation of which could trigger cellular senescence or apoptosis [144,147,148]. Of note, blocking either glycolysis or electron transport chain activity in MuSCs strongly prevents quiescence exit and the subsequent cell cycle re-entry, highlighting the importance of metabolic reprogramming during early MuSC activation [140,144]. Indeed, such metabolic reprogramming is conserved among multiple quiescent tissue-resident stem cells and progenitor cells during their activation, although the exact roles of individual metabolic pathways might be context-dependent [4,36,48,149].…”

“…MuSC quiescence exit describes the transition from quiescence into S phase of the first cell cycle, a process that takes ~36 h and is about four times longer than that for subsequent cell cycles [16,62,66,68,144]. The complexity of this transition is further evidenced by the recently identified early activation process, a short time window during which MuSCs undergo dramatic epigenetic and transcriptomic changes [38,161].…”