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Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies

1
Department of Family and Consumer Sciences, Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76706, USA
2
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(2), 520; https://doi.org/10.3390/jcm9020520
Received: 29 January 2020 / Accepted: 6 February 2020 / Published: 14 February 2020
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy. View Full-Text
Keywords: dilated cardiomyopathy; muscular dystrophy; calcium; heart; gene therapy; phospholamban; Serca2a; mdx; oxidative stress; membrane stabilization dilated cardiomyopathy; muscular dystrophy; calcium; heart; gene therapy; phospholamban; Serca2a; mdx; oxidative stress; membrane stabilization
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Law, M.L.; Cohen, H.; Martin, A.A.; Angulski, A.B.B.; Metzger, J.M. Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies. J. Clin. Med. 2020, 9, 520.

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