AMPKα1-LDH pathway regulates muscle stem cell self-renewal by controlling metabolic homeostasis.
EMBO J
; 36(13): 1946-1962, 2017 07 03.
Article
in En
| MEDLINE
| ID: mdl-28515121
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. 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stem Cells
/
Cell Differentiation
/
AMP-Activated Protein Kinases
/
Cell Self Renewal
/
Homeostasis
/
L-Lactate Dehydrogenase
/
Muscles
Limits:
Animals
Language:
En
Journal:
EMBO J
Year:
2017
Document type:
Article
Affiliation country:
France