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

Abstract

Skeletal muscle harbors a pool of stem cells called muscle satellite cells (MuSCs) that are mainly responsible for its robust regenerative capacities. Adult satellite cells are mitotically quiescent in uninjured muscles under homeostasis, but they exit quiescence upon injury to re-enter the cell cycle to proliferate. While most of the expanded satellites cells differentiate and fuse to form new myofibers, some undergo self-renewal to replenish the stem cell pool. Specifically, quiescence exit describes the initial transition of MuSCs from quiescence to the first cell cycle, which takes much longer than the time required for subsequent cell cycles and involves drastic changes in cell size, epigenetic and transcriptomic profiles, and metabolic status. It is, therefore, an essential period indispensable for the success of muscle regeneration. Diverse mechanisms exist in MuSCs to regulate quiescence exit. In this review, we summarize key events that occur during quiescence exit in MuSCs and discuss the molecular regulation of this process with an emphasis on multiple levels of intrinsic regulatory mechanisms. A comprehensive understanding of how quiescence exit is regulated will facilitate satellite cell-based muscle regenerative therapies and advance their applications in various disease and aging conditions.

Keywords: cell cycle re-entry; cell growth; checkpoints; mTORC1; quiescence exit; satellite cells.

Figure 1

Regulatory mechanisms controlling MuSC quiescence maintenance and quiescence exit (activation). The balance between MuSC quiescence and activation is actively regulated via multiple levels of mechanisms. These mechanisms function at signaling, epigenetic, transcriptional, post-transcriptional and metabolic levels, and together determine the fate of MuSCs. Notch signaling is highly active under quiescence, which is replaced by PI3K signaling upon activation. The epigenetic landscape also differs significantly between quiescent and activated MuSCs. The metabolic reprogramming upon activation is orchestrated with utilization of distinct cellular metabolic pathways. In terms of transcriptional landscape, MuSC activation is accompanied with a drastic reduction of Notch targets and induction of many immediate early genes (IEGs). The post-transcriptional mechanisms, including intron retention and the microRNA pathways, are also essential to maintain MuSC quiescence while preserving their rapid response to injury cues.

Figure 2

Schematic showing the progression of MuSC quiescence exit. Quiescent MuSCs are a pool of heterogeneous stem cells with different depths of quiescence. The more dormant MuSC population has slower activation kinetics but typically possesses stronger engraftment capacities. Early activation represents the first stage of quiescence exit, which happens within hours post tissue disruption. Key features of this stage are rapid induction of PI3K signaling and induction of many IEGs. This is followed by a long cell growth stage fueled by continuously increasing mTORC1 activity and coordinated metabolic reprogramming. PI3K and PAXBP1 are two critical regulators during quiescence exit that control an early activation checkpoint and a cell growth checkpoint, respectively.