Natural History of the HSA-LR mouse model for Myotonic Dystrophy Type 1 reveals age-dependent changes in myotonia, discharges, and RNA mis-splicing


Preclinical Trial Design & Biomarker Development

Poster Number: 150


Laurent Bogdanik, PhD, Orsolya Kiraly, PhD, Chia-yen Wu, PhD, Zachary Beaudry, Blaine Pattavina, Stephanie Williams, Saurabh Tata, Cathleen Lutz, PhD


1. The Jackson Laboratory, 2. The Jackson Laboratory, 3. The Jackson Laboratory, 5. The Jackson Laboratory, 8. The Jackson Laboratory

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.