MBNL1 overexpression is not sufficient to rescue the phenotypes in a mouse model of RNA toxicity.

Myotonic dystrophy type 1 (DM1) is caused by an expanded (CTG)n tract in the 3'UTR of the DM protein kinase (DMPK) gene. The RNA transcripts produced from the expanded allele sequester or alter the function of RNA-binding proteins (MBNL1, CUGBP1, etc.). The sequestration of MBNL1 results in RNA-splicing defects that contribute to disease. Overexpression of MBNL1 in skeletal muscle has been shown to rescue some of the DM1 features in a mouse model and has been proposed as a therapeutic strategy for DM1. Here, we sought to confirm if overexpression of MBNL1 rescues the phenotypes in a different mouse model of RNA toxicity. Using an inducible mouse model of RNA toxicity in which expression of the mutant DMPK 3'UTR results in RNA foci formation, MBNL1 sequestration, splicing defects, myotonia and cardiac conduction defects, we find that MBNL1 overexpression did not rescue skeletal muscle function nor beneficially affect cardiac conduction. Surprisingly, MBNL1 overexpression also did not rescue myotonia, though variable rescue of Clcn1 splicing and other splicing defects was seen. Additionally, contrary to the previous study, we found evidence for increased muscle histopathology with MBNL1 overexpression. Overall, we did not find evidence for beneficial effects from overexpression of MBNL1 as a means to correct RNA toxicity mediated by mRNAs containing an expanded DMPK 3'UTR.