AMPKα1-LDH pathway regulates muscle stem cell self-renewal by controlling metabolic homeostasis

EMBO J. 2017 Jul 3;36(13):1946-1962. doi: 10.15252/embj.201695273. Epub 2017 May 17.


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.

Keywords: glycolysis; metabolic shift; skeletal muscle regeneration; stem cell fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Differentiation*
  • Cell Self Renewal*
  • Glycolysis
  • Homeostasis*
  • L-Lactate Dehydrogenase / metabolism*
  • Mice
  • Mice, Knockout
  • Muscles / cytology*
  • Stem Cells / metabolism*


  • L-Lactate Dehydrogenase
  • AMPK alpha1 subunit, mouse
  • AMP-Activated Protein Kinases