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FOXO3 Promotes Quiescence in Adult Muscle Stem Cells during the Process of Self-Renewal
Open accessAbstract
Skeletal muscle stem cells, or "satellite cells" (SCs), are required for the regeneration of damaged muscle tissue. Although SCs self-renew during regeneration, the mechanisms that govern SC re-entry into quiescence remain elusive. We show that FOXO3, a member of the forkhead family of transcription factors, is expressed in quiescent SCs (QSCs). Conditional deletion of Foxo3 in QSCs impairs self-renewal and increases the propensity of SCs to adopt a differentiated fate. Transcriptional analysis of SCs lacking FOXO3 revealed a downregulation of Notch signaling, a key regulator of SC quiescence. Conversely, overexpression of Notch intracellular domain (NICD) rescued the self-renewal deficit of FOXO3-deficient SCs. We show that FOXO3 regulates NOTCH1 and NOTCH3 receptor expression and that decreasing expression of NOTCH1 and NOTCH3 receptors phenocopies the effect of FOXO3 deficiency in SCs. We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.
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“Consistent with previous reports of the role of FOXO factors in HSC, MuSC and NSC quiescence85–90, constitutive deletion of three of the FOXO genes (FOXO1, FOXO3 and FOXO4) in the MuSC lineage during development results in the impairment of postnatal establishment of the MuSC population and a more rapid MuSC depletion with age32.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [86]
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“For example, FOXO transcription factors integrate growth factors and stress signal transduction pathways, and may represent a ‘hub’ for the action of various systemic factors in stem cells in ageing brain, muscle, blood and intestine32,85–90.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [86]
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Metadata
- Authors
- Gopinath, S. D., Webb, A. E., Brunet, A., & Rando, T. A.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Rando, Thomas A.
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 2
- Issue
- 4
- Pages
- 414-426
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC3986584
- OpenAlex
- W2038069027
- Cited by
- 212
- References
- 46
- Citations by year
- 2026: 17 · 2025: 9 · 2024: 13 · 2023: 22 · 2022: 21 · 2021: 16 · 2020: 13 · 2019: 15 · 2018: 19 · 2017: 25 · 2016: 18 · 2015: 21 · 2014: 3
- FWCI
- 9.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002324, I01RX001222)
- Ellison Medical Foundation
- Glenn Foundation for Medical Research (P01 AG036695, R01 AR062185)
- Oregon Health and Science University
- Fondation pour la Recherche Médicale
- National Institutes of Health (AG023806, AG036695)
- University of Texas MD Anderson Cancer Center
- National Institute on Aging (R37AG023806, P01AG036695)
- National Cancer Institute (T32CA009302)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062185)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- FOXO3, skeletal muscle stem cells, satellite cells, quiescence, self-renewal, Notch signaling, Notch1, Notch3, muscle regeneration, differentiation, conditional gene deletion
- MeSH terms
- Forkhead Box Protein O3, Animals, Cell Differentiation, Regeneration, RNA, Messenger, Signal Transduction, Gene Expression, Resting Phase, Cell Cycle, Mice, Knockout, Muscle, Skeletal, Satellite Cells, Skeletal Muscle, Cell Proliferation, Mice, PAX7 Transcription Factor, Forkhead Transcription Factors, Receptors, Notch, Adult Stem Cells
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