Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy

Relizani, K., Mouisel, E., Giannesini, B., Hourde, C., Patel, K., Morales Gonzales, S., Julich, K., Vignaud, A., Pietri-Rouxel, F., Fortin, D., Garcia, L., Blot, S., Ritvos, O., Bendahan, D., Ferry, A., Ventura-Clapier, R., Schuelke, M. and Amthor, H. (2014) Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy. Molecular Therapy, 22 (8). pp. 1423-1433. ISSN 1525-0024 doi: 10.1038/mt.2014.90

Abstract/Summary

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 four months of 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 down-regulates 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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/46381
Identification Number/DOI	10.1038/mt.2014.90
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Uncontrolled Keywords	ActRIIB, myostatin, metabolic myopathy, muscle fatigue, oxidative phosphorylation, beta-oxidation, Duchenne muscular dystrophy, mdx mouse
Publisher	Nature Publishing Group
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