AMPKα1-LDH pathway regulates muscle stem cell self-renewal by controlling metabolic homeostasis.
EMBO J
; 36(13): 1946-1962, 2017 07 03.
Article
em 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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco
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Diferenciação Celular
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Proteínas Quinases Ativadas por AMP
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Autorrenovação Celular
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Homeostase
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L-Lactato Desidrogenase
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Músculos
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article