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

Marine Theret; Linda Gsaier; Bethany Schaffer; Gaëtan Juban; Sabrina Ben Larbi; Michèle Weiss-Gayet; Laurent Bultot; Caterina Collodet; Marc Foretz; Dominique Desplanches; Pascual Sanz; Zizhao Zang; Lin Yang; Guillaume Vial; Benoit Viollet; Kei Sakamoto; Anne Brunet; Bénédicte Chazaud; Rémi Mounier

doi:10.15252/embj.201695273

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.

Authors

Marine Theret^{1

2

3

4}, Linda Gsaier^{1

2

3}, Bethany Schaffer⁵, Gaëtan Juban^{1

2

3}, Sabrina Ben Larbi^{1

2

3}, Michèle Weiss-Gayet^{1

2

3}, Laurent Bultot^{6

7}, Caterina Collodet^{6

7}, Marc Foretz^{4

8

9}, Dominique Desplanches^{1

2

3}, Pascual Sanz¹⁰, Zizhao Zang¹¹, Lin Yang¹¹, Guillaume Vial¹², Benoit Viollet^{4

7

8}, Kei Sakamoto^{6

7}, Anne Brunet⁵, Bénédicte Chazaud^{1

2

3}, Rémi Mounier^{13

2

3}

Affiliations

¹ Institut Neuromyogène, Université Claude Bernard Lyon 1, Villeurbanne, France.
² INSERM U1217, Villeurbanne, France.
³ CNRS UMR 5310, Villeurbanne, France.
⁴ Université Paris Descartes, Paris, France.
⁵ Department of Genetic and the Cancer Biology Program, University of Stanford, Stanford, CA, USA.
⁶ Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
⁷ School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁸ INSERM U1016, Institut Cochin, Paris, France.
⁹ CNRS UMR 8104, Paris, France.
¹⁰ Instituto de Biomedecina de Valencia, CSIC, Valencia, Spain.
¹¹ Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
¹² INSERM U1042, Université Grenoble Alpes, La Tronche, France.
¹³ Institut Neuromyogène, Université Claude Bernard Lyon 1, Villeurbanne, France remi.mounier@univ-lyon1.fr.

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.

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*

Substances

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

Grants and funding

P01 NS097197/NS/NINDS NIH HHS/United States