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

Abstract

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:Utrn^+/-, 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. The mdx:Cmah^-/- 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 mdx and mdx:Cmah^-/- mice versus WT mice at 7 weeks. Tissue mineral density was also higher in mdx:Cmah^-/- mice at 3 and 7 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.This article has an associated First Person interview with the first author of the paper.

Keywords: Duchenne muscular dystrophy; Growth; Growth plate; Marrow adiposity; Micro-CT; Skeletal development.