The transcription factor Slug represses p16Ink4a and regulates murine muscle stem cell aging

Pei Zhu, Chunping Zhang, Yongxing Gao, Furen Wu, Yalu Zhou and Wen-Shu Wu ()
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Pei Zhu: University of Illinois at Chicago
Chunping Zhang: University of Illinois at Chicago
Yongxing Gao: The Johns Hopkins University School of Medicine
Furen Wu: University of Illinois at Chicago
Yalu Zhou: University of Illinois at Chicago
Wen-Shu Wu: University of Illinois at Chicago

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10479-4

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