Daunorubicin reduces MBNL1 titration by expanded CUG repeat RNA and rescues cardiac dysfunctions in a Drosophila model of myotonic dystrophy

Abstract

Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disorder caused by expression of mutant DMPK transcripts containing expanded CUG repeats. Pathogenic RNA sequesters the muscleblind-like (MBNL) proteins, causing alterations of RNA metabolism. Cardiac dysfunction represents the second most common cause of death in DM1 patients. However, the contribution of MBNL titration in DM1 cardiac dysfunction is unclear. We overexpressed Muscleblind (Mbl), Drosophila MBNL orthologue, in cardiomyocytes of DM1 model flies and observed a rescue of heart dysfunctions, which are characteristic of these model flies and resemble cardiac defects observed in patients. We also identified a drug, Daunorubicin hydrochloride, that directly binds to CUG repeats and alleviates Mbl titration in Drosophila DM1 cardiomyocytes, resulting into missplicing rescue and cardiac function recovery. These results demonstrate the relevance of Mbl titration by expanded CUG RNA in cardiac dysfunctions in DM1, and highlight the potential of strategies aimed at inhibit this protein-RNA interaction to recover normal cardiac function.