Background: Myotonic dystrophy (DM) is a multi-systemic genetic disorder caused by CUG/CCUG repeat RNAs that sequester MBNL RNA binding proteins. In addition to skeletal muscle phenotypes, individuals with DM often experience digestive symptoms including altered gut motility and bacterial overgrowth. These symptoms of DM are poorly understood in part due to inadequate animal model systems for studying them.
Objectives: We aimed to create stable zebrafish genetic models of DM. Zebrafish are well suited for the study of digestive phenotypes because gut motility can be studied directly in live transparent larvae, microbiota can be manipulated easily, and their high fecundity facilitates testing of candidate therapeutics.
Results: To mimic the molecular changes in DM, we generated zebrafish single, double, and triple homozygous mbnl1, mbnl2, and mbnl3 mutants as well as stable transgenic CUG-repeat expressing zebrafish. Zebrafish DM models exhibited widespread changes in alternative splicing, including many that were conserved in individuals with DM. Like mouse models, zebrafish DM models displayed decreased body size and impaired motor behavior. In addition, DM model fish exhibited increased gut inflammation that was dependent on the microbiota, suggesting altered digestive function and dysbiosis.
Conclusions: Our novel zebrafish models mimic general molecular and physical aspects of DM, and will be useful for studying the physical and molecular mechanisms that underlie DM digestive phenotypes, how bacteria contribute to them, and for testing the efficacy of candidate therapeutics.