ArticleMolecular therapy : the journal of the American Society of Gene Therapy2014
Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 70 citations in OpenAlex.
- Trial
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- Combinatorial Inhibition of Myostatin and Activin A Improves Femoral Bone Properties in the G610C Mouse Model of Osteogenesis Imperfecta.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2022Article
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- Targeting the myostatin signaling pathway to treat muscle loss and metabolic dysfunction.The Journal of clinical investigation · 2021Review
- Antimyostatin Treatment in Health and Disease: The Story of Great Expectations and Limited Success.Cells · 2021Review
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- A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities.Disease models & mechanisms · 2021Article
- p21-Activated Kinase 1 Is Permissive for the Skeletal Muscle Hypertrophy Induced by Myostatin Inhibition.Frontiers in physiology · 2021Article
- Diminution in sperm quantity and quality in mouse models of Duchenne Muscular Dystrophy induced by a myostatin-based muscle growth-promoting intervention.European journal of translational myology · 2020Article
- Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development.European journal of translational myology · 2020Article
- Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies.International journal of molecular sciences · 2020Review
- Loss of mitochondrial energetics is associated with poor recovery of muscle function but not mass following disuse atrophy.American journal of physiology. Endocrinology and metabolism · 2019Article
- Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling.Journal of cachexia, sarcopenia and muscle · 2019Article
- In silico prediction of short hairpin RNA and in vitro silencing of activin receptor type IIB in chicken embryo fibroblasts by RNA interference.Molecular biology reports · 2019Article
- A GDF11/myostatin inhibitor, GDF11 propeptide-Fc, increases skeletal muscle mass and improves muscle strength in dystrophic mdx mice.Skeletal muscle · 2019Article
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Authors and funding
18 authors at 9 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 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.
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