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...

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Autores: Chakraborty, Mouli, Selma-Soriano, Estela, Magny, Emile G., Couso, Juan Pablo, Pérez-Alonso, Manuel, Charlet-Berguerand, Nicolas, Artero, Rubén, Llamusí, Beatriz
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/191780
Acesso em linha:http://hdl.handle.net/10261/191780
Access Level:acceso abierto
Palavra-chave:Drosophila
Heart dysfunction
Myotonic dystrophy
Muscleblind
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spelling Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunctionChakraborty, MouliSelma-Soriano, EstelaMagny, Emile G.Couso, Juan PabloPérez-Alonso, ManuelCharlet-Berguerand, NicolasArtero, RubénLlamusí, BeatrizDrosophilaHeart dysfunctionMyotonic dystrophyMuscleblindUp 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.This study was co-funded by grants from the Ministerio de Economía y Competitividad (SAF2012-36854, including funds from FEDER) and ERA-Net E-Rare framework by ISCIII (PI12/03106 including funds from FEDER) upon the AES (R+D+I) National Plan of Spain to R.A. and B.L., respectively. Additional financial support was from project PI13/00386, by ISCIII co-financed by FEDER funds, to M.P.-A. M.C. was the recipient of a Santiago Grisolía award (GrisoliaP/2013/A/044).Peer reviewedCompany of BiologistsMinisterio de Economía y Competitividad (España)Instituto de Salud Carlos IIIEuropean Commission201920192015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/191780reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1242/dmm.021428Noinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1917802026-05-22T06:33:51Z
dc.title.none.fl_str_mv Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction
title Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction
spellingShingle Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction
Chakraborty, Mouli
Drosophila
Heart dysfunction
Myotonic dystrophy
Muscleblind
title_short 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_sort Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction
dc.creator.none.fl_str_mv Chakraborty, Mouli
Selma-Soriano, Estela
Magny, Emile G.
Couso, Juan Pablo
Pérez-Alonso, Manuel
Charlet-Berguerand, Nicolas
Artero, Rubén
Llamusí, Beatriz
author Chakraborty, Mouli
author_facet Chakraborty, Mouli
Selma-Soriano, Estela
Magny, Emile G.
Couso, Juan Pablo
Pérez-Alonso, Manuel
Charlet-Berguerand, Nicolas
Artero, Rubén
Llamusí, Beatriz
author_role author
author2 Selma-Soriano, Estela
Magny, Emile G.
Couso, Juan Pablo
Pérez-Alonso, Manuel
Charlet-Berguerand, Nicolas
Artero, Rubén
Llamusí, Beatriz
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
European Commission
dc.subject.none.fl_str_mv Drosophila
Heart dysfunction
Myotonic dystrophy
Muscleblind
topic Drosophila
Heart dysfunction
Myotonic dystrophy
Muscleblind
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.
publishDate 2015
dc.date.none.fl_str_mv 2015
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/191780
url http://hdl.handle.net/10261/191780
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1242/dmm.021428
No
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Company of Biologists
publisher.none.fl_str_mv Company of Biologists
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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