Molecular therapy, 2014-08, Vol.22 (8), p.1423-1433
2014
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Details
- Autor(en) / Beteiligte
- Titel
- Blockade of ActRIIB Signaling Triggers Muscle Fatigability and Metabolic Myopathy
- Ist Teil von
- Molecular therapy, 2014-08, Vol.22 (8), p.1423-1433
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 Phophorus Magnetic Resonance Spectroscopy (31P-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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1525-0016eISSN: 1525-0024DOI: 10.1038/mt.2014.90Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4435590
- Format
- –
- Schlagworte
- Activin Receptors, Type II - antagonists & inhibitors, Animals, Biochemistry, Molecular Biology, Cell Line, Clinical trials, Energy, Energy Metabolism - drug effects, Fatigue, Force, Gene Expression Regulation - drug effects, Human health and pathology, Human Umbilical Vein Endothelial Cells, Humans, Immunoglobulin Fc Fragments - pharmacology, Life Sciences, Male, Metabolism, Mice, Mice, Inbred mdx, Muscle function, Muscles - physiopathology, Muscular dystrophy, Muscular Dystrophy, Animal - physiopathology, Musculoskeletal system, Neuromuscular diseases, Original, Phosphorylation, Porins - metabolism, Signal Transduction - drug effects