a. Satellite cells, a type of muscle stem cell, remain quiescent under normal conditions. After muscle damage, satellite cells become activated and re-enter the cell cycle to produce muscle progenitor cells that regenerate new muscle fibres. They also self-renew to replenish the stem-cell population. b, Sousa-Victor et al.3 report that during ageing, geriatric satellite cells lose their reversible quiescent state owing to derepression of the gene encoding p16INK4a, a regulator of cellular senescence. Instead, they adopt a senescent-like state (becoming pre-senescent cells), which impairs the regeneration process, including activation, proliferation and self-renewal.Abstract:
Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16INK4a is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.