Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction
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 ventric...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2015-12-01
|
| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/8/12/1569 |
| _version_ | 1828396560522674176 |
|---|---|
| author | Mouli Chakraborty Estela Selma-Soriano Emile Magny Juan Pablo Couso Manuel Pérez-Alonso Nicolas Charlet-Berguerand Ruben Artero Beatriz Llamusi |
| author_facet | Mouli Chakraborty Estela Selma-Soriano Emile Magny Juan Pablo Couso Manuel Pérez-Alonso Nicolas Charlet-Berguerand Ruben Artero Beatriz Llamusi |
| author_sort | Mouli Chakraborty |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T08:32:13Z |
| format | Article |
| id | doaj.art-2fb806979e5b4416b927f1c2c3017756 |
| institution | Directory Open Access Journal |
| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-10T08:32:13Z |
| publishDate | 2015-12-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-2fb806979e5b4416b927f1c2c30177562022-12-22T01:56:04ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032015-12-018121569157810.1242/dmm.021428021428Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunctionMouli Chakraborty0Estela Selma-Soriano1Emile Magny2Juan Pablo Couso3Manuel Pérez-Alonso4Nicolas Charlet-Berguerand5Ruben Artero6Beatriz Llamusi7 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 School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK Translational Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 Rue Laurent Fries, 67400 Illkirch-Graffenstaden, France Translational Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain Translational Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain 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.http://dmm.biologists.org/content/8/12/1569DrosophilaHeart dysfunctionMyotonic dystrophyMuscleblindPentamidine |
| spellingShingle | Mouli Chakraborty Estela Selma-Soriano Emile Magny Juan Pablo Couso Manuel Pérez-Alonso Nicolas Charlet-Berguerand Ruben Artero Beatriz Llamusi Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction Disease Models & Mechanisms Drosophila Heart dysfunction Myotonic dystrophy Muscleblind Pentamidine |
| title | Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction |
| title_full | Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction |
| title_fullStr | Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction |
| title_full_unstemmed | Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction |
| title_short | Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction |
| title_sort | pentamidine rescues contractility and rhythmicity in a drosophila model of myotonic dystrophy heart dysfunction |
| topic | Drosophila Heart dysfunction Myotonic dystrophy Muscleblind Pentamidine |
| url | http://dmm.biologists.org/content/8/12/1569 |
| work_keys_str_mv | AT moulichakraborty pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction AT estelaselmasoriano pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction AT emilemagny pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction AT juanpablocouso pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction AT manuelperezalonso pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction AT nicolascharletberguerand pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction AT rubenartero pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction AT beatrizllamusi pentamidinerescuescontractilityandrhythmicityinadrosophilamodelofmyotonicdystrophyheartdysfunction |