Abstract
Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a CTG repeat disorder involving misbalance between two RNA binding factors, MBNL1 and CELF1. However, how DM1 condition translates into conduction disorders remains poorly understood. Here we simulated MBNL1 and CELF1 misbalance in the Drosophila heart and performed TU-tagging-based RNAseq of cardiac cells. We detected deregulations of several genes controlling cellular calcium levels, including increased expression of straightjacket/α2δ3, which encodes a regulatory subunit of a voltage-gated calcium channel. Straightjacket overexpression in the fly heart leads to asynchronous heartbeat, a hallmark of abnormal conduction, whereas cardiac straightjacket knockdown improves these symptoms in DM1 fly models. We also show that ventricular α2δ3 expression is low in healthy mice and humans, but significantly elevated in ventricular muscles from DM1 patients with conduction defects. These findings suggest that reducing ventricular straightjacket/α2δ3 levels could offer a strategy to prevent conduction defects in DM1.
Highlights
Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults (Theadom et al, 2014), is caused by a CTG triplet repeat expansion in the 3’ untranslated region of the dystrophia myotonica protein kinase gene
The Drosophila counterparts of Muscleblind-like 1 (MBNL1) and CUGBP- and ELAV-like family member 1 (CELF1), the Mbl and Bru-3 proteins, are both present in the fly heart cells, including contractile cardiomyocytes, and localize predominantly but not exclusively to the nuclei (Figure 1—figure supplement 1)
We tested heartbeat in flies in which Mbl was attenuated in parallel to Bru-3 overexpression (Figure 1— figure supplement 2) and found a moderate additive effect on conduction defects of these two deregulations present in DM1. These results show that the imbalance of Mbl/ MBNL1 and Bru-3/CELF1 in the fly heart increases the occurrence of asynchronous heartbeat
Summary
Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults (Theadom et al, 2014), is caused by a CTG triplet repeat expansion in the 3’ untranslated region of the dystrophia myotonica protein kinase (dmpk) gene. Data suggest that cardiac phenotypes, including conduction defects, are due to MBNL1/CELF1 misbalance It was shown in a DM1 mouse model that PKC phosphorylates CELF1 leading to increased CELF1 levels, whereas PKC inhibition caused CELF1 reduction and amelioration of cardiac dysfunction (Wang et al, 2009). We simulated pathogenic MBNL1/CELF1 misbalance in the fly heart by attenuating the Drosophila MBNL1 ortholog Muscleblind (Mbl) and by overexpressing the CELF1 counterpart Bruno-3 (Bru-3) (Picchio et al, 2018) This caused asynchronous heartbeat (anterior and posterior heart segments beating at different rates), which in Drosophila results from partial conduction block (Birse et al, 2010). Lowering a2d3 in ventricular cardiomyocytes could offer a potential treatment strategy for DM1-associated conduction defects and in particular intraventricular conduction delay (IVCD)
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