The transcription factor Slug represses p16Ink4a and regulates murine muscle stem cell aging
Open accessAbstract
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.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [42]
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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)
- PMC
- PMC6561969
- 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
- gold
- doi.org
- 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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