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. 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.

Source: EMBO Journal - July 3, 2017 Category: Molecular Biology Authors: Theret, M., Gsaier, L., Schaffer, B., Juban, G., Ben Larbi, S., Weiss-Gayet, M., Bultot, L., Collodet, C., Foretz, M., Desplanches, D., Sanz, P., Zang, Z., Yang, L., Vial, G., Viollet, B., Sakamoto, K., Brunet, A., Chazaud, B., Mounier, R. Tags: Metabolism, Stem Cells Articles Source Type: research