Cited by 66Muscle Physiology and DisordersTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

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

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Zhu, Pei, Zhang, Chunping, Gao, Yongxing, Wu, Furen, Zhou, Yalu, Wu, Wen-Shu·2019·Nature Communications

Abstract

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.

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  • Some old MuSCs become senescent, a state characterized by irreversible cell cycle arrest and secretion of cytokines and other proteins.

    “For example, some old MuSCs become senescent, a state characterized by irreversible cell cycle arrest and secretion of cytokines and other proteins (senescence-associated secreted phenotype)39–43.”

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Authors
Zhu, P., Zhang, C., Gao, Y., Wu, F., Zhou, Y., & Wu, W.-S.
Affiliations
  • University of Illinois Chicago (US)
  • Johns Hopkins University (US)
Venue
Nature Communications
Published
2019-06-12
Volume
10
Issue
1
Pages
2568-2568
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2950729524
Cited by
66
References
69
Citations by year
2026: 6 · 2025: 9 · 2024: 11 · 2023: 7 · 2022: 10 · 2021: 13 · 2020: 8 · 2019: 1 · 2018: 1
FWCI
2.65
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (1R01AG040182)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
Slug, p16INK4a, muscle stem cells, satellite cells, cellular senescence, muscle aging, self-renewal, transcriptional repression, muscle regeneration, zinc finger transcription factor
MeSH terms
Cell Self Renewal, Snail Family Transcription Factors, Aging, Animals, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Cellular Senescence, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, Models, Animal, Satellite Cells, Skeletal Muscle, Mice

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