Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy
Résumé
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
| Origine | Publication financée par une institution |
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