Mechanical and non-mechanical functions of Dystrophin can prevent cardiac abnormalities in Drosophila

Abstract

Dystrophin-deficiency causes cardiomyopathies and shortens the life expectancy of Duchenne and Becker muscular dystrophy patients. Restoring Dystrophin expression in the heart by gene transfer is a promising avenue to explore as a therapy. Truncated Dystrophin gene constructs have been engineered and shown to alleviate dystrophic skeletal muscle disease, but their potential in preventing the development of cardiomyopathy is not fully understood. In the present study, we found that either the mechanical or the signaling functions of Dystrophin were able to reduce the dilated heart phenotype of Dystrophin mutants in a Drosophila model. Our data suggest that Dystrophin retains some function in fly cardiomyocytes in the absence of a predicted mechanical link to the cytoskeleton. Interestingly, cardiac-specific manipulation of nitric oxide synthase expression also modulates cardiac function, which can in part be reversed by loss of Dystrophin function, further implying a signaling role of Dystrophin in the heart. These findings suggest that the signaling functions of Dystrophin protein are able to ameliorate the dilated cardiomyopathy, and thus might help to improve heart muscle function in micro-Dystrophin-based gene therapy approaches.

Keywords: AAV; AI; Adeno-associated virus; Aging; Arrhythmia index; BMD; Becker muscular dystrophy; CR; CT; Carboxy-terminal domain; Cysteine-rich domain; DCM; DGC; DMD; Dbr; Dg; Dilated cardiomyopathy; Duchene muscular dystrophy; Dys; Dystrobrevin; Dystroglycan; Dystrophin; Dystrophin-glycoprotein complex; Endothelial Nos; Grb2; Growth factor receptor-bound protein 2; HPs; Heart period; Heart periods; Inducible Nos; Micro-Dystrophins; Myofibrils; NO; Neuronal nitric oxide synthase; Nitric oxide; Nitric oxide synthase; SR; Sarcoplasmic reticulum; Syn; Syntrophin; Utrn; Utrophin; X-linked dilated cardiomyopathy; XLDCM; eNos; iNos; nNos.