Generación y caracterización de modelos en drosophila de disfunción cardiaca en distrofia miotónica

Resum

The thesis entitled “Generación y caracterización de modelos en Drosophila de disfunción cardiaca en distrofia miotónica” is done by combining three published articles. After respiratory distress, heart dysfunction is the second most common cause of fatality associated with the neuromuscular disease myotonic dystrophy (DM). Despite the central involvement of heart failure in DM, physiopathological studies on heart symptoms have been relatively scarce because few murine models faithfully reproduce the cardiac disease. Consequently, only a small number of candidate compounds have been evaluated in this specific phenotype. To help cover this gap Drosophila combines the amenability of its invertebrate genetics with the possibility of quickly acquiring physiological parameters suitable for meaningful comparisons with vertebrate animal models and humans. In this original work, I have generated and characterized the Drosophila models of cardiac dysfunction in myotonic dystrophy type 1 and type 2. Notably, flies expressing CUG or CCUG RNA in their hearts developed strong arrhythmias and had reduced fractional shortening, which correlates with similar phenotypes in DM patients. Overexpression of Muscleblind, which is abnormally sequestered by CUG and CCUG repeat RNA managed to strongly suppress arrhythmias and fractional shortening, thus demonstrating that Muscleblind depletion causes cardiac phenotypes in flies. Importantly, small molecules pentamidine and daunorubicin were able to rescue cardiac phenotypes by releasing Muscleblind from sequestration. Taken together, the thesis has shown that fly heart models have the potential to make important contributions to the understanding of the molecular causes of cardiac dysfunction in DM and in the quick assessment of candidate therapeutics.