Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy

K. Relizani (1) , E. Mouisel (2) , B. Giannesini (3) , C. Hourde (1) , K. Patel (4) , S. Morales Gonzalez (5) , K. Julich (5) , A. Vignaud (6) , F. Pietri-Rouxel (1, 7) , D. Fortin (8) , L. Garcia (9) , Stéphane Blot (10) , O. Ritvos (11) , D. Bendahan (3) , A. Ferry (7, 12) , R. Ventura-Clapier (13) , M. Schuelke (5) , H. Amthor (9, 7, 14)

1 Centre de recherche en Myologie – U974 SU-INSERM
2 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
3 CRMBM - Centre de résonance magnétique biologique et médicale
4 UOR - University of Reading
5 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
6 IMBI - Immunologie moléculaire et biothérapies innovantes
7 Institut de Myologie
8 University of Ottawa [Ottawa]
9 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
10 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
11 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
12 UFR Médecine UPCité - UFR Médecine [Santé] - Université Paris Cité
13 Signalisation et physiopathologie cardiaque
14 Hôpital Necker - Enfants Malades [AP-HP]

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 Pparbeta, Pgc1alpha, 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.

Mots clés: Human Umbilical Vein Endothelial Cells; Energy Metabolism/drug effects; inhibitors; Type II/*antagonists & Activin Receptors; Porins/metabolism; Signal Transduction/drug effects; Muscular Dystrophy; Muscles/*physiopathology; Immunoglobulin Fc Fragments/*pharmacology; Humans; Male; Animals; Mice; Cell Line; Inbred mdx; Gene Expression Regulation/drug effects; Animal/*physiopathology

Domaines: Biochimie, Biologie Moléculaire; Médecine humaine et pathologie

K. Relizani, E. Mouisel, B. Giannesini, C. Hourde, K. Patel, et al.. Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy. Molecular Therapy, 2014, 22 (8), pp.1423-1433. ⟨10.1038/mt.2014.90⟩. ⟨hal-02881194⟩