AMPKα1‐LDH pathway regulates muscle stem cell self‐renewal by controlling metabolic homeostasis |
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| Authors: | Marine Theret Gaëtan Juban Sabrina Ben Larbi Michèle Weiss‐Gayet Laurent Bultot Marc Foretz Dominique Desplanches Pascual Sanz Zizhao Zang Lin Yang Guillaume Vial Benoit Viollet Kei Sakamoto Anne Brunet Bénédicte Chazaud Rémi Mounier |
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| Affiliation: | 1. Institut Neuromyogène, Université Claude Bernard Lyon 1, Villeurbanne, France;2. INSERM U1217, Villeurbanne, France;3. CNRS UMR 5310, Villeurbanne, France;4. Université Paris Descartes, Paris, France;5. Nestlé Institute of Health Sciences SA, Lausanne, Switzerland;6. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;7. INSERM U1016, Institut Cochin, Paris, France;8. CNRS UMR 8104, Paris, France;9. Instituto de Biomedecina de Valencia, CSIC, Valencia, Spain;10. Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA;11. INSERM U1042, Université Grenoble Alpes, La Tronche, France;12. Department of Genetic and the Cancer Biology Program, University of Stanford, Stanford, CA, USA |
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| Abstract: | Control of stem cell fate to either enter terminal differentiation versus returning to quiescence (self‐renewal) is crucial for tissue repair. Here, we showed that AMP‐activated protein kinase (AMPK), the master metabolic regulator of the cell, controls muscle stem cell (MuSC) self‐renewal. AMPKα1?/? MuSCs displayed a high self‐renewal rate, which impairs muscle regeneration. AMPKα1?/? MuSCs showed a Warburg‐like switch of their metabolism to higher glycolysis. We identified lactate dehydrogenase (LDH) as a new functional target of AMPKα1. LDH, which is a non‐limiting enzyme of glycolysis in differentiated cells, was tightly regulated in stem cells. In functional experiments, LDH overexpression phenocopied AMPKα1?/? phenotype, that is shifted MuSC metabolism toward glycolysis triggering their return to quiescence, while inhibition of LDH activity rescued AMPKα1?/? MuSC self‐renewal. Finally, providing specific nutrients (galactose/glucose) to MuSCs directly controlled their fate through the AMPKα1/LDH pathway, emphasizing the importance of metabolism in stem cell fate. |
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| Keywords: | glycolysis metabolic shift skeletal muscle regeneration stem cell fate |
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