title: AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity.
abstract: AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.-Lantier, L., Fentz, J., Mounier, R., Leclerc, J., Treebak, J. T., Pehmøller, C., Sanz, N., Sakakibara, I., Saint-Amand, E., Rimbaud, S., Maire, P., Marette, A., Ventura-Clapier, R., Ferry, A., Wojtaszewski, J. F. P., Foretz, M., Viollet, B. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Louise
authors.initials: L
authors.lastname: Lantier
authors.affiliation: Section of Molecular Physiology, The August Krogh Centre, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Joachim
authors.initials: J
authors.lastname: Fentz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Rémi
authors.initials: R
authors.lastname: Mounier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Leclerc
authors.affiliation: Section of Molecular Physiology, The August Krogh Centre, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Treebak
authors.affiliation: Section of Molecular Physiology, The August Krogh Centre, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Christian
authors.initials: C
authors.lastname: Pehmøller
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Nieves
authors.initials: N
authors.lastname: Sanz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Iori
authors.initials: I
authors.lastname: Sakakibara
authors.affiliation: Laval University, Ste-Foy, Quebec, Canada;
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Saint-Amand
authors.affiliation: INSERM, U769, Université Paris Sud, Châtenay-Malabry, France; and.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rimbaud
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Pascal
authors.initials: P
authors.lastname: Maire
authors.affiliation: Laval University, Ste-Foy, Quebec, Canada;
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.affiliation: INSERM, U769, Université Paris Sud, Châtenay-Malabry, France; and.
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut de Myologie, INSERM, U974, CNRS UMR 7215, Université Pierre et Marie Curie, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.affiliation: Section of Molecular Physiology, The August Krogh Centre, Department of Nutrition, Exercise, and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U)1016, Institut Cochin, Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; benoit.viollet@inserm.fr.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D005947:Glucose / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology; D018763:Muscle Fatigue / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000502:physiology; D010805:Physical Conditioning, Animal; D010807:Physical Endurance / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: force production; glucose transport