AMPK alpha 1-LDH pathway regulates muscle stem cell self-renewal by controlling metabolic homeostasis

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. AMPK alpha 1(-/-) MuSCs displayed a high self-renewal rate, which impairs muscle regeneration. AMPK alpha 1(-/-) MuSCs showed a Warburg-like switch of their metabolism to higher glycolysis. We identified lactate dehydrogenase (LDH) as a new functional target of AMPK alpha 1. 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 alpha 1(-/-) phenotype, that is shifted MuSC metabolism toward glycolysis triggering their return to quiescence, while inhibition of LDH activity rescued AMPK alpha 1(-/-) MuSC self-renewal. Finally, providing specific nutrients (galactose/glucose) to MuSCs directly controlled their fate through the AMPK alpha 1/LDH pathway, emphasizing the importance of metabolism in stem cell fate.