The transcription factor Slug represses p16(Ink4a) and regulates murine muscle stem cell aging

Activation of the p16(Ink4a)-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. Here, we report that the zinc-finger transcription factor Slug is highly expressed in quiescent SCs of mice and functions as a direct transcriptional repressor of p16(Ink4a). Loss of Slug promotes derepression of p16(Ink4a) in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16(Ink4a) depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16(Ink4a) accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16(Ink4a) transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at advanced age. As p16(Ink4a) dysregulation is the chief cause for regenerative defects of human geriatric SCs, these findings highlight Slug as a potential therapeutic target for aging-associated degenerative muscle disease.