Disruption of the dystrophin-sarcoglycan complex (DGC) has been identified as the molecular basis for impaired sarcolemmal membrane integrity and increased cytosolic Ca2+ concentration [Ca2+]i in some muscular dystrophies (MDs). This increased [Ca2+]i contributes to myofiber death via activation of calpains (Ca2+-dependent neutral proteases). Moreover, the rate of Ca2+ sparks significantly increases in dystrophic myofibers, consistent with defective "leaky" SR Ca2+ release channels. Indeed, recent studies have identified RyR1 mutations that are genetically linked to MDs. We recently showed that S-nitrosylation of the type 1 ryanodine receptor (RyR1) in skeletal muscle causes FKBP12 (calstabin1) depletion from the channel complex resulting in SR Ca2+ leak that contributes to muscle weakness and damage in the murine mdx model of Duchenne muscular dystrophy. Treatment with S107, a novel small molecule derived from 1,4-benzothiazepines, that inhibits calstabin-1 depletion from the RyR1 complex, improved exercise capacity, muscle force and reduced muscle damage in dystrophic mice. The applicant proposes to test the hypothesis that "leaky" RyR1 and RyR2 channels due to hypernitrosylation of the channels are a common feature of MDs that involve disruption of the DCG. Furthermore, by preventing RyR1 and RyR2 leak using a novel compound, S107, the applicant will seek to reduce muscle damage, cardiac abnormalities, and improve exercise capacity in murine models of MD. The proposed studies are significant because they may identify a novel mechanism underlying intracellular Ca2+ leak that contributes to pathology in MD and could be a therapeutic target in patients.

Public Health Relevance

Muscular Dystrophy (MD) is a heterogeneous, genetic disease characterized by progressive weakness and degeneration of striated muscle, in particular the skeletal muscles that control movement. Despite important advances that have elucidated molecular mechanisms, therapy for most forms of MD remains supportive and prognosis is grave for many patients. Moreover, the side effects of the current therapies (steroids, immunosuppressants and anti-convulsants) can add to the morbidity of MD. It is possible that an improved understanding the pathophysiology of MD could lead to the development novel therapeutic approaches that could improve quality of life and prolong survival. This might be particularly important as definitive treatments such as gene replacement are being developed. The present project is designed to test a novel therapeutic target for MD, leaky ryanodine receptor/calcium release channels, and determine whether a new class of drugs called rycals that fix the leak in the channel improve exercise capacity in MD and prevent muscle damage in mouse models.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Boyce, Amanda T
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Zalk, Ran; Clarke, Oliver B; des Georges, Amédée et al. (2015) Structure of a mammalian ryanodine receptor. Nature 517:44-9
Marx, Steven O; Marks, Andrew R (2013) Dysfunctional ryanodine receptors in the heart: new insights into complex cardiovascular diseases. J Mol Cell Cardiol 58:225-31
Andersson, Daniel C; Marks, Andrew R (2010) Fixing ryanodine receptor Ca leak - a novel therapeutic strategy for contractile failure in heart and skeletal muscle. Drug Discov Today Dis Mech 7:e151-e157
Kushnir, Alexander; Betzenhauser, Matthew J; Marks, Andrew R (2010) Ryanodine receptor studies using genetically engineered mice. FEBS Lett 584:1956-65