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AMPK α1‐ LDH pathway regulates muscle stem cell self‐renewal by controlling metabolic homeostasis
Author(s) -
Theret Marine,
Gsaier Linda,
Schaffer Bethany,
Juban Gaëtan,
Ben Larbi Sabrina,
WeissGayet Michèle,
Bultot Laurent,
Collodet Caterina,
Foretz Marc,
Desplanches Dominique,
Sanz Pascual,
Zang Zizhao,
Yang Lin,
Vial Guillaume,
Viollet Benoit,
Sakamoto Kei,
Brunet Anne,
Chazaud Bénédicte,
Mounier Rémi
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695273
Subject(s) - ampk , microbiology and biotechnology , biology , glycolysis , stem cell , protein kinase a , amp activated protein kinase , warburg effect , cellular differentiation , biochemistry , metabolism , kinase , gene
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 (Mu SC ) self‐renewal. AMPK α1 −/− Mu SC s displayed a high self‐renewal rate, which impairs muscle regeneration. AMPK α1 −/− Mu SC s showed a Warburg‐like switch of their metabolism to higher glycolysis. We identified lactate dehydrogenase ( LDH ) as a new functional target of AMPK α1. 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 α1 −/− phenotype, that is shifted Mu SC metabolism toward glycolysis triggering their return to quiescence, while inhibition of LDH activity rescued AMPK α1 −/− Mu SC self‐renewal. Finally, providing specific nutrients (galactose/glucose) to Mu SC s directly controlled their fate through the AMPK α1/ LDH pathway, emphasizing the importance of metabolism in stem cell fate.