The NAD+-Dependent SIRT1 Deacetylase Translates a Metabolic Switch into Regulatory Epigenetics in Skeletal Muscle Stem Cells
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Stem cells undergo a shift in metabolic substrate utilization during specification and/or differentiation, a process that has been termed metabolic reprogramming. Here, we report that during the transition from quiescence to proliferation, skeletal muscle stem cells experience a metabolic switch from fatty acid oxidation to glycolysis. This reprogramming of cellular metabolism decreases intracellular NAD(+) levels and the activity of the histone deacetylase SIRT1, leading to elevated H4K16 acetylation and activation of muscle gene transcription. Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in SCs. Moreover, mice with muscle-specific inactivation of the SIRT1 deacetylase domain display reduced myofiber size, impaired muscle regeneration, and derepression of muscle developmental genes. Overall, these findings reveal how metabolic cues can be mechanistically translated into epigenetic modifications that regulate skeletal muscle stem cell biology.
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SIRT1 protects MuSC progeny from premature differentiation by regulating histone acetylation.
“SIRT1, a member of the sirtuin family, protects MuSC progeny from premature differentiation by regulating histone acetylation118”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [118]
In the event of injury, quiescent stem cells undergo a dynamic process of activation, generating biomass, restructuring cellular geometry, altering metabolism, and entering the cell cycle to produce progenitor daughters.
“In the event of injury, quiescent stem cells undergo a dynamic process of activation, generating biomass, restructuring cellular geometry, altering metabolism (Ryall et al., 2015), and entering the cell cycle to produce progenitor daughters (Brack and Rando, 2012).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Ryall et al., 2015
Forward moving cells have a higher velocity for protein translation and biogenesis genes, whereas backward moving cells have a higher velocity for mitochondrial respiration genes.
“This analysis reveals that forward moving cells have a higher velocity for protein translation and biogenesis genes, whereas backward moving cells have a higher velocity for mitochondrial respiration genes (Fig. S13D, Gene Ontology enrichments; Table S15), consistent with the upregulation of protein synthesis and involvement of oxidative phosphorylation in myogenic activation (Ryall et al., 2015).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Ryall et al., 2015
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- Authors
- Ryall, J. G., Dell’Orso, S., Derfoul, A., Juan, A., Zare, H., Feng, X., Clermont, D., Koulnis, M., Gutierrez-Cruz, G., Fulco, M., & Sartorelli, V.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Sartorelli, Vittorio
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 16
- Issue
- 2
- Pages
- 171-183
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4320668
- OpenAlex
- W2029054948
- Cited by
- 575
- References
- 57
- Citations by year
- 2026: 44 · 2025: 41 · 2024: 45 · 2023: 55 · 2022: 60 · 2021: 60 · 2020: 63 · 2019: 45 · 2018: 51 · 2017: 57 · 2016: 34 · 2015: 20
- FWCI
- 26.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (ZIAAR041164)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- SIRT1, histone deacetylase, skeletal muscle stem cells, metabolic reprogramming, NAD+, H4K16 acetylation, histone acetylation, glycolysis, fatty acid oxidation, myogenesis, muscle regeneration, muscle fiber size, epigenetic regulation
- MeSH terms
- Acetylation, Animals, Histones, NAD, Stem Cells, Muscle, Skeletal, Epigenesis, Genetic, Mice, Sirtuin 1
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