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.

In vitro-generated human muscle reserve cells are heterogeneous for Pax7 with distinct molecular states and metabolic profiles

“…We also showed an increased expression of active AMPK⍺1 in human MuRC that correlate with an increase fatty acid uptake. Together, these results demonstrate that human MuRC operate a metabolic shift from glycolysis toward FAO, a process known to contribute to the preservation of muscle stem cell quiescence [5,22,25,42]. Metabolic factors are identified as playing a critical role in regulating MuSC fate decisions and functions that can also influence the efficacy of stem cell-based therapies [22,41,43,44].…”

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

“…This analysis also revealed dysregulation of Notch signaling and epigenetic pathways (See also Supplemental Fig. 3), which are key players in quiescence 19,20,[50][51][52][53] . Interestingly, cross-talk between BMP signaling and Notch has been reported in other systems 54 .…”

Intravital microscopy of satellite cell dynamics and their interaction with myeloid cells during skeletal muscle regeneration

“…Additionally, niche factors from the extracellular matrix or myofibers also contribute to maintaining MuSC quiescence (79,81). The MuSC activation is a complex process involving early activation [or quiescence-to-activation (Q-A) transition], cell growth, and S phase reentry, which typically takes about 36 hours (82,83). This process encompasses a series of molecular and morphological events, including epigenetic modifications (e.g., H3K4me3 and H3K27ac) (84), changes in transcriptome (e.g., quick induction of stress response genes) (84)(85)(86), and mitochondrial biogenesis and cell volume increase (6,7,48,49).…”