Muscular dystrophy (mdx) mice with enhanced voluntary exercise: Mining genetic modifiers

Patients with the same genetic mutation who differ in disease severity may possess genetic modifying factors. Such genetic modifiers have been identified for neuromuscular disorders; many of these have been found from mouse studies. The Collaborative Cross (CC) is a resource with the potential to effectively map genetic modifiers more effectively than previously available methods. Derived from eight genetically diverse founder mouse strains, the genome of each CC offspring strain is a mosaic of chromosomal segments inherited randomly from the founders. As a proxy measure of skeletal muscle function, we analysed voluntary running wheel activity of over 50 CC mouse strains at two different ages (6 weeks and 6 months). Marked phenotypic variation was seen across strains for all related traits measured (distance run per day, maximum speed, average speed, and time spent running per day). A select number of strains were chosen to breed with dystrophin-deficient muscular dystrophy (mdx) mice, and we evaluated voluntary running wheel activity of the resulting progeny. Progeny of some strains performed equal to, or worse than, mdx mice on the standard C57BL/10 background. However, the dystrophin-deficient progeny of one of the highest performing CC strains had significantly improved voluntary exercise performance. Comparison of the CC strains' genomes allowed mapping of a key modifier gene to a small chromosome region that is currently being scrutinised. Microarray analysis of skeletal muscles from “rescued” and “standard” mdx mice indicates a relatively small number of differentially expressed genes between the two cohorts. Pathway analysis of differentially expressed genes highlights the Parkinson's pathway. The genetic modifier/s for improved voluntary exercise ability by mdx mice could be targeted for modulation as a potential therapeutic avenue for muscular dystrophy.