Claire Wood MRC Clinical fellowship

The muscular dystrophy x-linked (mdx) mouse is commonly used as a mouse model of Duchenne muscular dystrophy (DMD). Its phenotype is, however, mild and other mouse models have been explored. The mdx:cmah mouse carries a human-like mutation in the Cmah gene and has a severe muscle phenotype, but its growth and bone development are unknown. In this study we compared male mdx, mdx:utr+/-, mdx:cmah-/- and wild-type (WT) mice at 3, 5 and 7 weeks of age to determine the suitability of the mdx:cmah-/- mouse as a model for assessing growth and skeletal development in DMD. Mdx:cmah mice were lighter than WT mice at 3, but heavier at 7 weeks (p=0.02) and showed an increased growth rate at 5 weeks (p=0.007). Cortical bone fraction as assessed by micro-computed tomography was greater in both mdx and mdx:cmah mice v WT mice at 7 weeks (p<0.05).Tissue mineral density was also higher in mdx:cmah mice at 3 (p<0.05) and 7 (p<0.01) weeks. Gene profiling of mdx:cmah bone identified increased expression of Igf1, Igf1r and Vegfa. Both the mdx and mdx:cmah mice showed an increased proportion of regulated bone marrow adipose tissue (BMAT) but a reduction in constitutive BMAT. The mdx:cmah mice show evidence of catch-up growth and more rapid bone development. This pattern does not mimic the typical DMD growth trajectory and therefore the utility of the mdx:cmah mouse for studying growth and skeletal development in DMD is limited. Further studies of this model may however shed light on the phenomenon of catch-up growth.