Abstract
Activation of the p16Ink4a-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 p16Ink4a. Loss of Slug promotes derepression of p16Ink4a in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16Ink4a depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16Ink4a accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16Ink4a transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at advanced age. As p16Ink4a 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.
Highlights
Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity
Slug deletion causes a defect in muscle regeneration
By comparing with several other muscle resident cell types including fibro-adipogenic progenitors (FAPs), pan-lymphocytes (LCs), and epithelial cells (ECs), in which the role of Slug is well characterized, we found that Slug is most highly expressed in quiescent SCs (Fig. 2a), and its expression was slightly reduced in activated SCs and markedly decreased after SCs were differentiated into myotubes (Fig. 2b)
Summary
Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. 1234567890():,; Skeletal muscle is a homeostatic tissue that is capable of making up turnover caused by daily wear-and-tear as well as regenerating upon damage Derepression of p16Ink4a switches geriatric SCs from reversible quiescence into senescence, leading to incompetency of activation on muscle injury even in a youthful environment[5] Those cell intrinsic components regulating p16Ink4a expression in SCs remain largely unknown. We establish Slug, a member of zinc-finger transcription factor in the Slug/Snail superfamily, as a transcriptional repressor of p16Ink4a in SCs. Akin to mice with aging, loss of Slug endows adult SCs features of pre-senescence by largely inducing p16Ink4a expression, triggering apparent regenerative defects during serial muscle damage. Our results highlight Slug as a key target for aging-associated degenerative muscle disease
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