Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction

Abstract

Up to 80% of myotonic dystrophy type 1 (DM1) patients will develop cardiac abnormalities at some point during the progression of their disease. The most common of them are varying degrees of heart blockage characterized by conduction defects and supraventricular and ventricular tachycardia, resulting in a high risk of sudden cardiac death. Despite its importance, very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. Morphologically, expression of 250 CUG repeats caused abnormalities in the parallel alignment of the spiral myofibrils in dissected fly hearts revealed by phalloidin staining. Moreover, combined immunofluorescence and in situ hybridization of Muscleblind and CUG repeats, respectively, confirmed detectable ribonuclear foci and Muscleblind sequestration, characteristic features of DM1, exclusively in flies expressing the expanded CTG repeats. Similarly to what has been reported in human DM1 patients, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function and reduced heart tube diameters and contractility in the model flies. As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind and reduced ribonuclear formation in the Drosophila heart but rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats.