AMPK?1-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 (MuSC) self-renewal. AMPK?1^-/- MuSCs displayed a high self-renewal rate, which impairs muscle regeneration. AMPK?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?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?1^-/- phenotype, that is shifted MuSC metabolism toward glycolysis triggering their return to quiescence, while inhibition of LDH activity rescued AMPK?1^-/- MuSC self-renewal. Finally, providing specific nutrients (galactose/glucose) to MuSCs directly controlled their fate through the AMPK?1/LDH pathway, emphasizing the importance of metabolism in stem cell fate.

SUBMITTER: Theret M 

PROVIDER: S-EPMC5494470 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature