title: Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle.
abstract: Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn(-/-) mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn(-/-) mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn(-/-) mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn(-/-) mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM)/Paul Sabatier University, UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Obesity Research Laboratory, Toulouse, France; Sorbonne Universités, Universités Européennes, l'Université Pierre et Marie Curie (UPMC), Paris 06, Myology Center of Research and Institut National de la Santé et de la Recherche Médicale, UMR S974 and Centre National de la Recherche Scientifique, FRE 3617 and Institut de Myologie, Paris, France;
authors: Etienne
authors: E
authors: Mouisel
authors: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany; Laboratoire "End:icap", UFR des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, France;
authors: Karima
authors: K
authors: Relizani
authors: INSERM UMR 902, Université d'Evry-Val d'Essonne, Evry, France;
authors: Laurence
authors: L
authors: Mille-Hamard
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, Paris, France;
authors: Raphaël
authors: R
authors: Denis
authors: Sorbonne Universités, Universités Européennes, l'Université Pierre et Marie Curie (UPMC), Paris 06, Myology Center of Research and Institut National de la Santé et de la Recherche Médicale, UMR S974 and Centre National de la Recherche Scientifique, FRE 3617 and Institut de Myologie, Paris, France; Laboratory of Exercise Physiology, University of Savoie, Chambery, France;
authors: Christophe
authors: C
authors: Hourdé
authors: UPMC, Paris 06, Sorbonne Universités, UMR Centre National de la Recherche Scientifique (CNRS) Biological Adaptation and Ageing, Paris, France;
authors: Onnik
authors: O
authors: Agbulut
authors: School of Biological Sciences, University of Reading, Reading, United Kingdom;
authors: Ketan
authors: K
authors: Patel
authors: Sorbonne Universités, Universités Européennes, l'Université Pierre et Marie Curie (UPMC), Paris 06, Myology Center of Research and Institut National de la Santé et de la Recherche Médicale, UMR S974 and Centre National de la Recherche Scientifique, FRE 3617 and Institut de Myologie, Paris, France;
authors: Ludovic
authors: L
authors: Arandel
authors: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany;
authors: Susanne
authors: S
authors: Morales-Gonzalez
authors: Généthon, Evry, France;
authors: Alban
authors: A
authors: Vignaud
authors: Laboratoire "End:icap", UFR des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, France; Laboratoire International Associé - Biothérapies Appliquées aux Handicaps Neuromusculaires, Centre Scientifique de Monaco, Monaco;
authors: Luis
authors: L
authors: Garcia
authors: Sorbonne Universités, Universités Européennes, l'Université Pierre et Marie Curie (UPMC), Paris 06, Myology Center of Research and Institut National de la Santé et de la Recherche Médicale, UMR S974 and Centre National de la Recherche Scientifique, FRE 3617 and Institut de Myologie, Paris, France; Université Paris Descartes, Paris, France;
authors: Arnaud
authors: A
authors: Ferry
authors: Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC 4413, Paris, France; CNRS, EAC 4413, Paris, France; and.
authors: Serge
authors: S
authors: Luquet
authors: INSERM UMR 902, Université d'Evry-Val d'Essonne, Evry, France;
authors: Véronique
authors: V
authors: Billat
authors: INSERM UMR 769, Université Paris-Sud, Châtenay-Malabry, France.
authors: Renée
authors: R
authors: Ventura-Clapier
authors: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany;
authors: Markus
authors: M
authors: Schuelke
authors: Sorbonne Universités, Universités Européennes, l'Université Pierre et Marie Curie (UPMC), Paris 06, Myology Center of Research and Institut National de la Santé et de la Recherche Médicale, UMR S974 and Centre National de la Recherche Scientifique, FRE 3617 and Institut de Myologie, Paris, France; Laboratoire "End:icap", UFR des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, France; Laboratoire International Associé - Biothérapies Appliquées aux Handicaps Neuromusculaires, Centre Scientifique de Monaco, Monaco; helge.amthor@uvsq.fr.
authors: Helge
authors: H
authors: Amthor
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D005838:Genotype; D006019:Glycolysis; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism; D009119:Muscle Contraction; D018763:Muscle Fatigue; D018482:Muscle, Skeletal / Q000378:metabolism*; D055435:Myostatin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010807:Physical Endurance; D012420:Running; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C525912:Mstn protein, mouse; D055435:Myostatin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D019344:Lactic Acid; D010751:Phosphopyruvate Hydratase
keywords: exercise capacity; mitochondria; muscle fatigue; myostatin; oxidative phosphorylation; peroxisome proliferatior-activated receptor