A comparison of the bone and growth phenotype of <i>mdx</i>, <i>mdx:Cmah−/−</i> and <i>mdx:Utrn</i> <i>+/−</i> murine models with the C57BL/10 wild-type mouse

Abstract

The muscular dystrophy X-linked (<i>mdx</i>) 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 <i>mdx:Cmah^-/-</i> mouse carries a human-like mutation in the <i>Cmah</i> gene and has a severe muscle phenotype, but its growth and bone development are unknown. In this study, we compared male <i>mdx</i>, <i>mdx:Utrn</i>^+/-, <i>mdx:Cmah^-/-</i> and wild-type (WT) mice at 3, 5 and 7 weeks of age to determine the suitability of the <i>mdx:Cmah^-/-</i> mouse as a model for assessing growth and skeletal development in DMD. The <i>m</i><i>dx:Cmah^-/-</i> mice were lighter than WT mice at 3 weeks, but heavier at 7 weeks, and showed an increased growth rate at 5 weeks. Cortical bone fraction as assessed by micro-computed tomography was greater in both <i>mdx</i> and <i>mdx:</i><i>C</i><i>mah^-/-</i> mice versus WT mice at 7 weeks. Tissue mineral density was also higher in <i>mdx:Cmah^-/-</i> mice at 3 and 7 weeks. Gene profiling of <i>mdx:Cmah^-/-</i> bone identified increased expression of <i>Igf1</i>, <i>Igf1r</i> and <i>Vegfa</i> Both the <i>mdx</i> and <i>mdx:Cmah^-/-</i> mice showed an increased proportion of regulated bone marrow adipose tissue (BMAT) but a reduction in constitutive BMAT. The <i>mdx:Cmah^-/-</i> 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 <i>mdx:Cmah^-/-</i> 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.This article has an associated First Person interview with the first author of the paper.