Intrinsic and extrinsic mechanisms regulating satellite cell function

Abstract

Muscle stem cells, termed satellite cells, are crucial for skeletal muscle growth and regeneration. In healthy adult muscle, satellite cells are quiescent but poised for activation. During muscle regeneration, activated satellite cells transiently re-enter the cell cycle to proliferate and subsequently exit the cell cycle to differentiate or self-renew. Recent studies have demonstrated that satellite cells are heterogeneous and that subpopulations of satellite stem cells are able to perform asymmetric divisions to generate myogenic progenitors or symmetric divisions to expand the satellite cell pool. Thus, a complex balance between extrinsic cues and intrinsic regulatory mechanisms is needed to tightly control satellite cell cycle progression and cell fate determination. Defects in satellite cell regulation or in their niche, as observed in degenerative conditions such as aging, can impair muscle regeneration. Here, we review recent discoveries of the intrinsic and extrinsic factors that regulate satellite cell behaviour in regenerating and degenerating muscles.

Keywords: Aging; Asymmetric division; Cell cycle regulation; Muscle stem cell; Myogenesis; Quiescence; Regeneration; Satellite cell; Self-renewal; Skeletal muscle.

Fig. 1.

The satellite cell and its niche. Satellite cells are located juxtaposed to mature muscle fibers in a quiescent state. Upon activation by extrinsic factors, satellite cells re-enter the cell cycle and proliferate to generate sufficient numbers of progeny to form new myofibers. Micrographs show Pax7-expressing (red) quiescent (A) and activated (B) satellite cells on cultured single myofibers. The schematics beneath represent the quiescent and activated satellite cells in their niche and enumerate the nuclear and surface molecular markers associated with each state.

Fig. 2.

Regulation of the cell cycle in satellite cells. In resting conditions, intrinsic regulators of the cell cycle maintain satellite cells in a reversible and quiescent G₀ state. Activated satellite cells then re-enter the cell cycle, either directly or via an intermediate state referred to as G_Alert. After activation, satellite cells can exit the cell cycle and return to quiescence by upregulating Spry1 or by increasing Notch signalling. Proliferating myoblasts also exit the cell cycle to differentiate into myocytes and progress into the myogenic lineage.

Fig. 3.

Satellite cell fate decisions. Activated satellite stem cells (Pax7⁺, Myf5^–, MyoD^–) can undergo symmetric divisions to expand the satellite stem cell population, or asymmetric divisions to maintain the stem cell population and generate myogenic progenitors. Satellite cells can also commit to the myogenic lineage and proliferate to give rise to committed myogenic progenitors (Pax7⁺, Myf5⁺ and/or MyoD⁺). Myogenic progenitors are able to asymmetrically divide or directly differentiate into myocytes (Myog⁺), which fuse and form new myofibers.

Fig. 4.

Satellite cells in aging. In young muscle, a critical balance between lineage commitment and self-renewal is maintained during regeneration. By contrast, aged muscles show increased lineage commitment (solid arrows) to myogenic progenitors (orange cells) and a lack of self-renewal (dashed arrows), resulting in impaired regeneration and slow exhaustion of the satellite cell reserve (green cells). Satellite cells from very old (‘geriatric’) muscles enter senescence and lose their ability to re-enter the cell cycle.