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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: C.L.W., S.C.W., S.F.A., C.F.; Methodology: C.L.W., K.J.S., R.v.t.H., W.P.C., S.D., S.F.A., C.F.; Formal analysis: C.L.W., K.J.S., R.v.t.H., W.P.C., C.F.; Investigation: C.L.W.; Resources: C.L.W.; Data curation: C.L.W.; Writing - original draft: C.L.W., W.P.C., C.F.; Writing - review & editing: C.L.W., K.J.S., R.v.t.H., W.P.C., S.D., V.S., S.C.W., S.F.A., C.F.; Supervision: V.S., S.C.W., S.F.A., C.F.; Project administration: S.F.A., C.F.; Funding acquisition: C.L.W., V.S., S.C.W., S.F.A., C.F.
Funding
C.L.W. is funded by the Medical Research Council/Muscular Dystrophy UK (MDUK) (MR/N020588/1). C.F. is grateful to the Biotechnology and Biological Sciences Research Council (BBSRC) for Institute Strategic Programme Grant Funding BB/P0137321. W.P.C. is funded by the Medical Research Council (MR/M021394) and supported by a Chancellor's Fellowship from the University of Edinburgh. W.P.C. and K.J.S. are also supported by the Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund.
Supplementary information
Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.040659.supplemental
- Received May 26, 2019.
- Accepted November 12, 2020.
- © 2020. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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