P.311 - Detailed natural history of the mdx-DBA model

Abstract

Mdx-BL10 mice are, despite their very mild pathology, the most commonly used model for Duchenne muscular dystrophy. Mdx mice on a DBA2/J genetic background (mdx-DBA) are more severely affected due to their dysfunctional Anxa6 and Ltbp4 genes (respectively involved in regeneration and fibrosis). Detailed knowledge on the natural disease history and standardized outcome measures are critical for preclinical studies, but are lacking for mdx-DBA mice. To address this, we assessed functional performance (fore-limb grip strength and wire and grid hanging tests) in n = 10 mdx-DBA and DBA2/J wildtype mice of both genders, twice monthly for a duration of 34 weeks and compared histopathology with similar sized sedentary groups. Muscle pathology between sedentary and functionally challenged mice did not differ, indicating that the functional test regime was not detrimental. In all functional tests, performance of mdx-DBA was severely impaired compared to wild type and interestingly, mdx-DBA females outperformed males. Respiratory function assessed at 7, 14 and 34 weeks of age was also affected in mdx-DBA mice. Creatine kinase levels were elevated in mdx-DBA mice, but lower than those of mdx-BL10 mice. Histopathology of the gastrocnemius, triceps, diaphragm and heart was compared between mdx-DBA, mdx-BL10 and wild type mice and revealed fibrosis, centralized nuclei, altered fiber size distribution and calcifications for both mdx models, but was more severe in mdx-DBA mice. The diaphragm was the most severely affected muscle. Expression of regenerative, immunological, fibrotic and adipose genes was upregulated in dystrophic mice. We are currently assessing the impact of forced treadmill running on pathology in mdx-DBA and mdx-BL10 mice, and the applicability of MRI to non-invasively monitor pathology. Our studies offer a comprehensive natural history data set which will be useful in the design of standardized tests and future pre-clinical studies in mdx-DBA mice.