Duchenne Muscular Dystrophy is a severe degenerative muscle disease characterized by loss of ambulation at 10 years of age, and death in the third decade of life. There is no treatment other than corticosteroids, which have severe side effects that limit the duration of use. DMD is caused by mutations in the X-linked dystrophin gene. Gene correction approaches are being studied aggressively but are unlikely to be in wide use in the near future. Affordable treatments that slow muscle degeneration are urgently needed now until effective gene correction techniques become widely available and cost effective. We have robust proof-of-concept evidence that the HMG CoA-reductase inhibitor, Simvastatin, markedly improves the dystrophic phenotype in skeletal and cardiac muscle in the mdx mouse model of DMD. This novel finding might be considered unexpected since statins are known to occasionally cause myopathy and, as a consequence, are contraindicated for use in individuals with muscle diseases, including DMD. However, long-term treatment of mdx mice with Simvastatin dramatically reduces plasma creatine kinase levels, increases diaphragm specific force and improves cardiac diastolic function. First, we will evaluate the dose response of two statins, Simvastatin and Rosuvastatin, in mdx mice using randomized, double blind, placebo-controlled studies. Established methods will be used to examine improvements in muscle contractile function and histological abnormalities in diaphragm and extensor digitorum longus muscles. In a second aim, the ability of statins to reverse cardiac and diaphragm dysfunction in aged mdx mice will be studied. Finally, we will determine if statins improve the lifespan of severely dystrophic mdx:utrophin double knockout mice. The goal of these studies is to obtain robust data, using rigorous methodology, that support further clinical development of statins as a treatment of DMD and possibly other muscular dystrophies.

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Duchenne Muscular Dystrophy is a severe and lethal muscle degeneration disease for which there is no treatment. We provide evidence using the mdx mouse model that treatment with statins markedly improves the dystrophic features of skeletal and cardiac muscle. This surprising result, given that statins themselves sometimes cause muscle problems, suggests a novel therapeutic pathway for treatment of DMD and possibly other muscle diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Nuckolls, Glen H
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University of Washington
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Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L et al. (2016) Simvastatin offers new prospects for the treatment of Duchenne muscular dystrophy. Rare Dis 4:e1156286
Whitehead, Nicholas P; Bible, Kenneth L; Kim, Min Jeong et al. (2016) Validation of ultrasonography for non-invasive assessment of diaphragm function in muscular dystrophy. J Physiol 594:7215-7227
Whitehead, Nicholas P (2016) Enhanced autophagy as a potential mechanism for the improved physiological function by simvastatin in muscular dystrophy. Autophagy 12:705-6
Allen, David G; Whitehead, Nicholas P; Froehner, Stanley C (2016) Absence of Dystrophin Disrupts Skeletal Muscle Signaling: Roles of Ca2+, Reactive Oxygen Species, and Nitric Oxide in the Development of Muscular Dystrophy. Physiol Rev 96:253-305
Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L et al. (2015) A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy. Proc Natl Acad Sci U S A 112:12864-9