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

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 (Mu SC ) self‐renewal. AMPK α1 −/− Mu SC s displayed a high self‐renewal rate, which impairs muscle regeneration. AMPK α1 −/− Mu SC s showed a Warburg‐like switch of their metabolism to higher glycolysis. We identified lactate dehydrogenase ( LDH ) as a new functional target of AMPK α1. LDH , which is a non‐limiting enzyme of glycolysis in differentiated cells, was tightly regulated in stem cells. In functional experiments, LDH overexpression phenocopied AMPK α1 −/− phenotype, that is shifted Mu SC metabolism toward glycolysis triggering their return to quiescence, while inhibition of LDH activity rescued AMPK α1 −/− Mu SC self‐renewal. Finally, providing specific nutrients (galactose/glucose) to Mu SC s directly controlled their fate through the AMPK α1/ LDH pathway, emphasizing the importance of metabolism in stem cell fate. image The master regulator of cellular energy homeostasis, AMPK α1, regulates muscle regeneration by acting on lactate dehydrogenase ( LDH ) activity and thus the oxidative phosphorylation versus aerobic glycolysis switch that controls differentiation/self‐renewal of muscle stem cells. AMPK α1 deficiency in Mu SC s strongly increases their self‐renewal, impairing tissue repair. Shifting MuSC metabolism towards glycolysis triggers self‐renewal via AMPKα1 pathway. Activation of AMPKα1 down‐regulates LDH activity and MuSC return to quiescence. High activity of LDH, a new functional target of AMPKα1, triggers MuSC self‐renewal.