title: Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction.
abstract: Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage of varying degrees. Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries 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, as 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 humans with DM1, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function, reduced heart tube diameters and reduced 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 from the CUG RNA repeats and reduced ribonuclear formation in the Drosophila heart, but also rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats.
authors.affiliation: Translational Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain Department of Genetics and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Dr Moliner 50, Burjasot 46100, Spain.
authors.forename: Mouli
authors.initials: M
authors.lastname: Chakraborty
authors.affiliation: Department of Genetics and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Dr Moliner 50, Burjasot 46100, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Selma-Soriano
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK.
authors.forename: Emile
authors.initials: E
authors.lastname: Magny
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Couso
authors.affiliation: Translational Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain Department of Genetics and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Dr Moliner 50, Burjasot 46100, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pérez-Alonso
authors.affiliation: Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 Rue Laurent Fries, 67400 Illkirch-Graffenstaden, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.affiliation: Translational Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain Department of Genetics and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Dr Moliner 50, Burjasot 46100, Spain ruben.artero@uv.es.
authors.forename: Ruben
authors.initials: R
authors.lastname: Artero
authors.affiliation: Translational Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain Department of Genetics and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, Dr Moliner 50, Burjasot 46100, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Llamusi
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects*; D008136:Longevity / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009223:Myotonic Dystrophy / Q000473:pathology / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism; D010419:Pentamidine / Q000494:pharmacology*; D010641:Phenotype; D016019:Survival Analysis; D013599:Systole / Q000187:drug effects; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D009687:Nuclear Proteins; C109271:mbl protein, Drosophila; D010419:Pentamidine
keywords: Drosophila; Heart dysfunction; Muscleblind; Myotonic dystrophy; Pentamidine