Modulation of muscle stem cell function through fasting
Abstract/Contents
- Abstract
- Fasting is a dietary restriction paradigm that promotes stress resistance, modulates tissue function, and extends lifespan in a variety of organisms. Some of the benefits of fasting are attributed to its ability to influence stem cell function, though the effects of fasting on muscle stem cells (MuSCs) and muscle regeneration are unknown. Here, we show that fasting increases the depth of MuSC quiescence, driving them into a state of deep quiescence (DQ) that is characterized by heightened stress resistance and delayed cell cycle entry. While DQ is not conducive to rapid muscle repair, DQ MuSCs are resistant to apoptotic stimuli, including oxidative stress, irradiation, nutrient deprivation, and proliferative stress. DQ MuSCs also exhibit improved transplantation potency, reliably outcompeting co-transplanted MuSCs from ad lib fed animals in competitive transplantation assays. Mechanistically, induction of MuSC DQ is dependent on the nutrient- and stress- responsive mTORC1 pathway. Indeed, downregulation of mTORC1 is both necessary and sufficient for induction of DQ, as revealed by pharmacological and MuSC specific genetic manipulations. Furthermore, ketosis, a physiological adaptation to fasting, contributes to the effects of fasting on MuSCs. The ketone body β hydroxybutyrate (BHB) downregulates mTORC1 and drives DQ in MuSCs from fed animals in a p53 dependent manner. Indeed, pharmacological activation of p53 phenocopies the effects of BHB on MuSCs, and BHB-induced DQ is abrogated in MuSCs that lack p53. We conclude that the effects of exogenous ketosis derive from the established role of BHB as an endogenous histone deacetylase (HDAC) inhibitor, as pharmacological HDAC inhibition mimics the effects of fasting on MuSCs. These findings are consistent with numerous reports of increased stress resistance in response to fasting, and they establish ketosis as a novel physiological regulator of stem cell quiescence and resilience
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Both, Andries Pieter |
|---|---|
| Degree supervisor | Rando, Thomas A |
| Thesis advisor | Rando, Thomas A |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Chan, Charles K. F. (Charles Kwok Fai), 1975-2024 |
| Thesis advisor | Palmer, Theo |
| Degree committee member | Brunet, Anne, 1972- |
| Degree committee member | Chan, Charles K. F. (Charles Kwok Fai), 1975-2024 |
| Degree committee member | Palmer, Theo |
| Associated with | Stanford University, Department of Stem Cell Biology and Regenerative Medicine |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Andries Pieter Both |
|---|---|
| Note | Submitted to the Department of Stem Cell Biology and Regenerative Medicine |
| Thesis | Thesis Ph.D. Stanford University 2021 |
| Location | https://purl.stanford.edu/yj470kq3695 |
Access conditions
- Copyright
- © 2021 by Andries Pieter Both
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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