MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model

Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the DMPK gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explore MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and mis-regulated alternative splicing and gene expression. While robust, rescue was partial compared to reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations, and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis. TREDT960I (Hom)/ MHCrtTA (Hemi) (CUG960) mice used in this RNA-seq study were separated into 6 groups, 3 experimental cohorts with AAV9-delivered heart-specific expression of 3XFLAG-MBNL1 and/or 3XMYC-MBNL2, as well as three control cohorts (on dox, on/off dox, and no dox control). For all cohorts except no dox cohort, CUG960 mice were put on dox since post-natal day 1. The three experimental cohorts received AAV9 through tail vein injection at 9 weeks of age and remained on dox as the on dox cohort till last time point (21 weeks of age). For the on/off dox cohort, the mice were taken off dox feed at 9 weeks of age and remained on normal chow till last time point. Ventricular and atrial tissues of all cohorts were collected at 12 weeks post-delivery (21 weeks of age) and three samples from each cohort were used for RNA isolations.