title: Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy.
abstract: Myostatin regulates skeletal muscle size via the activin receptor IIB (ActRIIB). However, its effect on muscle energy metabolism and energy-dependent muscle function remains largely unexplored. This question needs to be solved urgently since various therapies for neuromuscular diseases based on blockade of ActRIIB signaling are being developed. Here, we show in mice, that 4-month pharmacological abrogation of ActRIIB signaling by treatment with soluble ActRIIB-Fc triggers extreme muscle fatigability. This is associated with elevated serum lactate levels and a severe metabolic myopathy in the mdx mouse, an animal model of Duchenne muscular dystrophy. Blockade of ActRIIB signaling downregulates porin, a crucial ADP/ATP shuttle between cytosol and mitochondrial matrix leading to a consecutive deficiency of oxidative phosphorylation as measured by in vivo Phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS). Further, ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparβ, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders.
authors.affiliation: Université Pierre et Marie Curie, Institut de Myologie, Unité mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France; Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany; UFR des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Relizani
authors.affiliation: Université Pierre et Marie Curie, Institut de Myologie, Unité mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France; Current address: Inserm UMR 1048, Université Paul Sabatier, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Mouisel
authors.affiliation: Aix-Marseille Université, Centre National de la Recherche Scientifique, Centre de Resonance Magnetique Biologique et Medicale UMR 7339, Marseille, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Giannesini
authors.affiliation: Université Pierre et Marie Curie, Institut de Myologie, Unité mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hourdé
authors.affiliation: School of Biological Sciences, University of Reading, Reading, UK.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Morales Gonzalez
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Jülich
authors.affiliation: Université Pierre et Marie Curie, Institut de Myologie, Unité mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France; Généthon, 1 bis rue de l'Internationale, Evry, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.affiliation: Université Pierre et Marie Curie, Institut de Myologie, Unité mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Piétri-Rouxel
authors.affiliation: INSERM U 769, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Fortin
authors.affiliation: UFR des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia
authors.affiliation: Unité de Neurologie, Ecole Nationale Vétérinaire d'Alfort, Université Paris Est, Créteil, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.affiliation: Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Ritvos
authors.affiliation: Aix-Marseille Université, Centre National de la Recherche Scientifique, Centre de Resonance Magnetique Biologique et Medicale UMR 7339, Marseille, France.
authors.forename: David
authors.initials: D
authors.lastname: Bendahan
authors.affiliation: Université Pierre et Marie Curie, Institut de Myologie, Unité mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France; Université Paris Descartes, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.affiliation: INSERM U 769, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany. Electronic address: markus.schuelke@charite.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: Université Pierre et Marie Curie, Institut de Myologie, Unité mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, Paris, France; UFR des Sciences de la Santé, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France; Service Génétique Médicale, CHU Necker-Enfants Malades, Université Paris Descartes, Paris, France. Electronic address: helge.amthor@uvsq.fr.
authors.forename: Helge
authors.initials: H
authors.lastname: Amthor
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009132:Muscles / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000503:physiopathology*; D018272:Porins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007141:Immunoglobulin Fc Fragments; D018272:Porins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B