Ampk Alpha 1-Ldh Pathway Regulates Muscle Stem Cell Self-Renewal By Controlling Metabolic Homeostasis
EMBO JOURNAL(2017)
摘要
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.
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关键词
glycolysis, metabolic shift, skeletal muscle regeneration, stem cell fate
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