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AMPK α1‐ LDH pathway regulates muscle stem cell self‐renewal by controlling metabolic homeostasis

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Theret, Marine | Gsaier, Linda | Schaffer, Bethany | Juban, Gaëtan | Ben Larbi, Sabrina | Weiss‐gayet, Michèle | Bultot, Laurent | Collodet, Caterina | Foretz, Marc | Desplanches, Dominique | Sanz, Pascual | Zang, Zizhao | Yang, Lin | Vial, Guillaume | Viollet, Benoit | Sakamoto, Kei | Brunet, Anne | Chazaud, Bénédicte | Mounier, Rémi

Edité par CCSD ; EMBO Press -

International audience. 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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