Muscle Stem Cell Quiescence: Controlling Stemness by Staying Asleep.

Muscle stem cells (MuSCs) are tissue-resident stem cells required for growth and repair of skeletal muscle, that are otherwise maintained in a cell-cycle-arrested state called quiescence. While quiescence was originally believed to be a state of cellular inactivity, increasing evidence suggests that quiescence is dynamically regulated and contributes to stemness, the long-term capacity to maintain regenerative functions. Here, we review the current understanding of MuSC quiescence and highlight recently discovered molecular markers, which differentiate depth of quiescence and influence self-renewal capacity. We also discuss how quiescent MuSCs integrate paracrine factors from their niche and dynamically regulate cell signaling, metabolism and proteostasis as they anticipate physiological needs, and how perturbing these cues during aging impairs muscle regeneration. MuSCs are located on muscle fibers in a reversible cell-cycle-arrested state called quiescence. Quiescent MuSCs are molecularly and functionally heterogeneous and can be stratified in subpopulations with different dynamics of activation and regenerative potential. Maintenance and return to quiescence are regulated by interdependent extrinsic and intrinsic cues that coordinate the regenerative capacity of MuSCs and influence their ability to self-renew. MuSC stemness is the ability to perform efficient cell fate decisions to self-renew and to generate myogenic progenitors for long-term regenerative potential. Quiescence is a way to regulate stemness by preventing MuSC exhaustion. Aging perturbs cell-autonomous and niche-dependent mechanisms that alter MuSC quiescence and stemness, and impair their long-term regenerative capacity. [ABSTRACT FROM AUTHOR]