Myotonic Dystrophy, Type I is caused by a trinucleotide repeat expansion in the DMPK gene. Insertion of a human, expanded allele of DMPK in the mouse genome has proven a difficult way to model the pathology; however, the HSA-LR model, carrying the repeat expansion in a simplified transgene, recapitulates many aspects of the clinical presentation and is the work-horse of preclinical drug development. With the goal to inform future drug trials by providing a selection of adequate phenotypic tests, and a time course of the various phenotypes, we characterized the natural history of this model. We recorded longitudinally, from 1 to 8 months of age, the grip strength, isometric muscle force, muscle relaxation, and electric discharges in cohorts of aging mice, and characterized the RNA mis-splicing early, and late in the disease.
Body weight, grip strength and isometric muscle force were not different between HSA-LR homozygotes and wild type mice over the course of the study. Interestingly, using the foot-plate method to measure the torque of the tibialis anterior, we observed a robust phenotype present before the mice reach two months of age. Both the relaxation phenotype and the frequency of myotonic discharge recorded by EMG, peaked in severity between 4 and 6 months of age, and decreased afterward. This progression correlated with the severity of the RNA mis-splicing, which was decreased at 8 months, compared to 2 months.
In summary, our longitudinal study identifies a novel approach to measure the myotonia in the HSA-LR model for DM1 in the in vivo foot-pedal force measurement platform, and illustrates that aging these mice is not necessary to observe clinically-relevant phenotypes. These findings may inform more accurate preclinical drug development studies for DM1.