Researchers of the Translational Genomics Group of the Universitat de València and of the Health Research Institute of the Clinical Hospital INCLIVA, directed by professor Rubén Artero and professor Beatriz Llamusí, have published a pioneering study to know the molecular cause of the cardiac alterations in myotonic dystrophy (MD).
Published in the scientific journal ‘‘Disease Models and Mechanisms’, the study analyses the cardiac dysfunction of the disease in an animal biomedical model, the ‘Drosophila melanogaster’ fly or vinegar fly, and proposes pentamidine as a compound that reduces arrhythmia in insects as well as other effects which are present in dystrophy.
In spite of being a rare disease, the MD constitutes the most common kind of muscular dystrophy in adults. Its origin is the mutation of the DMPK gene, which provokes an increase in the number of repetitions of the CTG triplet, which goes from 5-34 copies to several hundreds, fact that provokes the apparition and the development of the disease. Dystrophy is characterised by a reduction of the muscle mass and a multi-system disorder that involves cardiac and endocrinal problems as well as problems in the nervous system.
In this study (‘Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction’), published in the end of 2015, the team directed by Rubén Artero and Beatriz Llamusí studied and analysed cardiac parameters like contractility and rhythmicity, altered in myotonic dystrophy. “The technology and method used in these studies in ‘Drosophila’ are unique at a national level and may be applied to other cardiac diseases with a genetic background”, affirm the experts.
Despite key role of the cardiac system in MD, very few studies have focused in guessing the molecular cause of this cardiac dysfunction in the disease and in proving the effect of compounds with therapeutic potential. The Valencian group has confirmed that pentamidine is a compound which partially rescues cardiac phenotype. Phenotypes are those observable features in an organism, which are the result of the interaction of its genetic background with the environment.
Generally, cardiac problems, which in dystrophy usually precede muscular ones, are present in the 80% of individuals with MD1 (the most serious one of the two types) and are the second cause of death, after respiratory failure. Three types of cardiac alterations can be observed in these patients: defects in conduction, arrhythmia and mechanical diastolic or systolic dysfunction. The model applied to the ‘Drosophila’ fly has reproduced these symptoms and has permitted the study of its molecular basis and its response to medicines.
In the research that has led to publication of the article, ‘Drosophila melanogaster’ flies were fed with pentamidine, and showed a reduction of the arrhythmia and an improvement in the contractility. Nonetheless, diastolic and systolic function were altered, which in other case suggests that the effect of this substance is limited.
In conclusion, this model is useful to identify new molecular mechanisms that cause the cardiac disorders and to test the effectiveness of different therapeutic approaches which until now, had only been tested in the skeletal muscle.
This study was funded by the Ministry of Economy and Competitiveness, FEDER fund, the European Union programme for the research in rare diseases and the Instituto de Salud Carlos III.
Article
Mouli Chakraborty, Estela Selma-Soriano, Emile Magny, Juan Pablo Couso, Manuel Perez-Alonso, Nicolas Charlet-Berguerand, Ruben Artero, and Beatriz Llamusi: ‘Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction’. Disease Models & Mechanisms (2015) 8, 1569-1578. Doi:10.1242/dmm.021428
Last update: 18 de january de 2016 11:41.
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