Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling
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Abstract
Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here, we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet or exogenously administered, promotes a deep quiescent state in muscle stem cells (MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Furthermore, we show that ketone bodies, specifically β-hydroxybutyrate, directly promote MuSC deep quiescence via a nonmetabolic mechanism. We show that β-hydroxybutyrate functions as an HDAC inhibitor within MuSCs, leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.
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Fasting enhances MuSC resilience to a variety of stresses.
“In muscle, fasting, while impairing the regenerative activity of MuSCs, enhances their resilience to a variety of stresses215.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [215]
The beneficial effects of fasting on MuSC resilience can be mimicked by a ketogenic diet or by direct administration of ketone bodies.
“The beneficial effects of fasting on MuSC resilience can be mimicked by a ketogenic diet or by direct administration of ketone bodies215.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [215]
Fasting impairs the regenerative activity of MuSCs.
“In muscle, fasting, while impairing the regenerative activity of MuSCs, enhances their resilience to a variety of stresses215.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [215]
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Leibowitz, B. J., Yang, L., Liang, W., Buchanan, M. E., Rachid, M., Parise, R. A., Beumer, J. H., Eiseman, J. L., Schoen, R. E., Zhang, L., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aam7610 · Cited by 51 · see citing works
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Flagged first, then by citations
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- Ling Liu, Cheung TH, C.G. and R.T. (2016). Isolation of Skeletal Muscle Stem Cells by Fluorescence-Activated Cell Sorting. Natture Protoc. 10, 1612– 1624. PMC4793971 26401916
Cited by
Sorted by citations
Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
Self-citationGasdermin D-mediated metabolic crosstalk promotes tissue repair
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- Authors
- Benjamin, D. I., Both, P., Benjamin, J. S., Nutter, C. W., Tan, J. H., Kang, J., Machado, L. A., Klein, J. D. D., de Morree, A., Kim, S., Liu, L., Dulay, H., Feraboli, L., Louie, S. M., Nomura, D. K., & Rando, T. A.
- Affiliations
- Stanford Medicine (US)
- University of California, Berkeley (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Rando, Thomas A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 34
- Issue
- 6
- Pages
- 902-918.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC9177797
- OpenAlex
- W4280490566
- Cited by
- 79
- References
- 86
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 20 · 2023: 13 · 2022: 8
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Buck Institute for Research on Aging (T32AG000266-21)
- National Institutes of Health (1 T32 GM 119995-1 A1)
- U.S. Department of Veterans Affairs (P01 AG036695, R01 AR073248, R37 AG023806)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- fasting, muscle stem cells, ketone bodies, beta-hydroxybutyrate, ketosis, ketogenic diet, muscle regeneration, refeeding, HDAC1, p53, histone acetylation, quiescence
- MeSH terms
- Fasting, Muscles, Tumor Suppressor Protein p53, 3-Hydroxybutyric Acid, Myoblasts
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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