Satellite cells in ageing: use it or lose it

Abstract

Individuals that maintain healthy skeletal tissue tend to live healthier, happier lives as proper muscle function enables maintenance of independence and actuation of autonomy. The onset of skeletal muscle decline begins around the age of 30, and muscle atrophy is associated with a number of serious morbidities and mortalities. Satellite cells are responsible for regeneration of skeletal muscle and enter a reversible non-dividing state of quiescence under homeostatic conditions. In response to injury, satellite cells are able to activate and re-enter the cell cycle, creating new cells to repair and create nascent muscle fibres while preserving a small population that can return to quiescence for future regenerative demands. However, in aged muscle, satellite cells that experience prolonged quiescence will undergo programmed cellular senescence, an irreversible non-dividing state that handicaps the regenerative capabilities of muscle. This review examines how periodic activation and cycling of satellite cells through exercise can mitigate senescence acquisition and myogenic decline.

Keywords: activation; ageing; exercise; muscle stem cell; quiescence; satellite cell.

Figure 1.

Satellite cell quiescence versus activation. Satellite stem (Pax7⁺:Myf5⁻) and committed cells (Pax7⁺:Myf5⁺) are able to exit the cell cycle and arrest in a reversible quiescent G₀ state. Satellite stem and committed cells are primed for rapid cell cycle reentry by transitioning to a second reversible quiescent state called G_Alert. Committed satellite cells in G_Alert begin transcribing downstream MRFs Myf5 and MyoD. Satellite cells in G_Alert are primed to quickly respond to regenerative demands by entering the cell cycle faster than G₀ quiescent satellite cells. Active progenitor cells initiate the terminal differentiation programme to upregulate MyoG and Mrf4 in myoblasts and myocytes before fusion into myotubes.

Figure 2.

Healthy quiescence requires periodic activation. (a) Prolonged quiescence is met with detrimental effects, including high proteotoxicity, mitochondrial dysfunction, genomic instability and impaired regeneration. As satellite cells age, they are prone to prolonged states of quiescence during times of inactivity. (b) Quiescent satellite cells accumulate defects in the form of misfolded proteins, mitochondrial damage, reactive oxygen species (ROS) and DNA damage, and begin to express senescence markers. (c) Activation and mitosis of satellite cells induced through exercise or injury upregulates several processes that actively clear cellular waste, including the ubiquitin/proteasome pathway (UPP), autophagy/mitophagy and the DNA damage response (DDR). Passive dilution of cellular waste is also achieved through increased cytoplasm during mitosis. (d) During the return to homeostasis, satellite cells re-enter quiescence, exhibiting lower levels of proteotoxicity, healthy mitochondria, intact genomic integrity and a high regenerative potential.