title: Mitochondrial impairment induced by postnatal ActRIIB blockade does not alter function and energy status in exercising mouse glycolytic muscle in vivo.
abstract: Because it leads to a rapid and massive muscle hypertrophy, postnatal blockade of the activin type IIB receptor (ActRIIB) is a promising therapeutic strategy for counteracting muscle wasting. However, the functional consequences remain very poorly documented in vivo. Here, we have investigated the impact of 8-wk ActRIIB blockade with soluble receptor (sActRIIB-Fc) on gastrocnemius muscle anatomy, energy metabolism, and force-generating capacity in wild-type mice, using totally noninvasive magnetic resonance imaging (MRI) and dynamic(31)P-MRS. Compared with vehicle (PBS) control, sActRIIB-Fc treatment resulted in a dramatic increase in body weight (+29%) and muscle volume (+58%) calculated from hindlimb MR imaging, but did not alter fiber type distribution determined via myosin heavy chain isoform analysis. In resting muscle, sActRIIB-Fc treatment induced acidosis and PCr depletion, thereby suggesting reduced tissue oxygenation. During an in vivo fatiguing exercise (6-min repeated maximal isometric contraction electrically induced at 1.7 Hz), maximal and total absolute forces were larger in sActRIIB-Fc treated animals (+26 and +12%, respectively), whereas specific force and fatigue resistance were lower (-30 and -37%, respectively). Treatment with sActRIIB-Fc further decreased the maximal rate of oxidative ATP synthesis (-42%) and the oxidative capacity (-34%), but did not alter the bioenergetics status in contracting muscle. Our findings demonstrate in vivo that sActRIIB-Fc treatment increases absolute force-generating capacity and reduces mitochondrial function in glycolytic gastrocnemius muscle, but this reduction does not compromise energy status during sustained activity. Overall, these data support the clinical interest of postnatal ActRIIB blockade.
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, 13385, Marseille, France; and.
authors.forename: Nelly
authors.initials: N
authors.lastname: Béchir
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, 13385, Marseille, France; and.
authors.forename: Émilie
authors.initials: É
authors.lastname: Pecchi
authors.affiliation: Université de Versailles Saint-Quentin-en-Yvelines, UFR des sciences de la santé, INSERM U1179, LIA BAHN CSM, SQY Therapeutics, 78180 Montigny-le-Bretonneux, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Relizani
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, 13385, Marseille, France; and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Vilmen
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, 13385, Marseille, France; and.
authors.forename: Yann
authors.initials: Y
authors.lastname: Le Fur
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, 13385, Marseille, France; and.
authors.forename: Monique
authors.initials: M
authors.lastname: Bernard
authors.affiliation: Université de Versailles Saint-Quentin-en-Yvelines, UFR des sciences de la santé, INSERM U1179, LIA BAHN CSM, SQY Therapeutics, 78180 Montigny-le-Bretonneux, France.
authors.forename: Helge
authors.initials: H
authors.lastname: Amthor
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, 13385, Marseille, France; and.
authors.forename: David
authors.initials: D
authors.lastname: Bendahan
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Résonance Magnétique Biologique et Médicale, UMR 7339, 13385, Marseille, France; and benoit.giannesini@univ-amu.fr.
authors.forename: Benoît
authors.initials: B
authors.lastname: Giannesini
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects*; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010759:Phosphorus Isotopes; D010805:Physical Conditioning, Animal; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
chemical_list: D010759:Phosphorus Isotopes; D011993:Recombinant Fusion Proteins; C000601041:sActRIIB-Fc fusion protein; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B; D018995:Myosin Heavy Chains
keywords: activin type IIB receptor; fatigue; force; myostatin; skeletal muscle hypertrophy