Transient hypoxia followed by progressive reoxygenation is required for muscle repair
Open accessAbstract
Muscle stem cells (MuSCs) are essential for skeletal muscle repair. Following injury, MuSCs reside in low oxygen environments until muscle fibers and vascularization are restablished. The dynamics of oxygen levels during the regenerative process and its impact on muscle repair has been underappreciated. We confirm that muscle repair is initiated in a low oxygen environment followed by gradual reoxygenation. Strikingly, when muscle reoxygenation is limited by keeping mice under systemic hypoxia, muscle repair is impaired and leads to the formation of hypotrophic myofibers. Sustained hypoxia decreases the ability of MuSCs to differentiate and fuse independently of HIF-1α or HIF-2α. Prolonged hypoxia specifically affects the circadian clock by increasing Rev-erbα expression in MuSCs. Using pharmacological tools, we demonstrate that Rev-ERBα negatively regulates myogenesis by reducing late myogenic cell fusion under prolonged hypoxia. Our results underscore the critical role of progressive muscle reoxygenation after transient hypoxia in coordinating proper myogenesis through Rev-ERBα.
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Cites
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Hypoxia requires Notch signaling to maintain the undifferentiated cell state
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Cellular dynamics in the muscle satellite cell niche
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“Among these actors, the transcription factor Bmal1 (Brain and Muscle ARNT-Like 1) has been shown to regulate MYOD expression and myo fi ber formation to support skeletal muscle homeostasis and repair (Andrews et al, 2010).”
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Skeletal Muscle Hypoxia-inducible Factor-1 and Exercise
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- Authors
- Quétin, M., Der Vartanian, A., Dubois, C., Berthier, J., Ledoux, M., Michineau, S., Drayton-Libotte, B., Prola, A., Sotiropoulos, A., Relaix, F., & Gervais, M.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Gervais, Marianne
- ORCID
- Venue
- EMBO Reports
- Published
- 2026-01-07
- Volume
- 27
- Issue
- 4
- Pages
- 954-974
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC12936113
- OpenAlex
- W7118839259
- Cited by
- 1
- References
- 8
- Citations by year
- 2026: 1
- FWCI
- 2.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- French Muscular Dystrophy Association (Translamuscle II (#19507))
- Agence Nationale de la Recherche (MyoStemVasc (ANR-17-CE14-0018-01))
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Meat and Animal Product Quality
- Keywords
- muscle repair, muscle stem cells, skeletal muscle regeneration, hypoxia, reoxygenation, systemic hypoxia, myogenesis, NR1D1, circadian clock, HIF-1α, HIF-2α
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