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.
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.
|des Georges, AmÃ©dÃ©e; Clarke, Oliver B; Zalk, Ran et al. (2016) Structural Basis for Gating and Activation of RyR1. Cell 167:145-157.e17|
|Yuan, Qi; Yang, Jingyi; Santulli, Gaetano et al. (2016) Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS. Proc Natl Acad Sci U S A 113:8532-7|
|Zalk, Ran; Clarke, Oliver B; des Georges, AmÃ©dÃ©e et al. (2015) Structure of a mammalian ryanodine receptor. Nature 517:44-9|
|Santulli, Gaetano; Marks, Andrew R (2015) Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging. Curr Mol Pharmacol 8:206-22|
|Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino et al. (2015) Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Invest 125:1968-78|
|Waning, David L; Mohammad, Khalid S; Reiken, Steven et al. (2015) Excess TGF-Î² mediates muscle weakness associated with bone metastases in mice. Nat Med 21:1262-71|
|Rullman, Eric; Andersson, Daniel C; Melin, Michael et al. (2013) Modifications of skeletal muscle ryanodine receptor type 1 and exercise intolerance in heart failure. J Heart Lung Transplant 32:925-9|
|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|
|Liu, Xiaoping; Betzenhauser, Matthew J; Reiken, Steve et al. (2012) Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction. Cell 150:1055-67|
|Andersson, Daniel C; Meli, Albano C; Reiken, Steven et al. (2012) Leaky ryanodine receptors in Ã½Ã½-sarcoglycan deficient mice: a potential common defect in muscular dystrophy. Skelet Muscle 2:9|
Showing the most recent 10 out of 15 publications