Short stature and osteoporosis are common in DMD. Glucocorticoids slow disease progression but are associated with further growth retardation and skeletal fragility. The muscular dystrophy x-linked (mdx) mouse is the most commonly used animal model of DMD. However, the phenotype is relatively mild and few medications that have shown therapeutic benefit in the mdx have translated clinically. The utrophin heterozygous mdx mice might be more appropriate but their growth and bone phenotype have not been investigated. We tested the hypothesis that: Mouse models of DMD (mdx and mdx:utr) have an intrinsic abnormality of linear growth and skeletal development. A cross-sectional study of 49 mice sacrificed at 3,5 and 7 weeks was performed. Mdx/mdx:utr mice were obtained from Jax, alongside C57BL/10 controls(WT). Growth was assessed twice weekly, forelimb grip strength testing performed, CK measured and histopathology assessed using H+E tibialis anterior sections. Tibiae were scanned using SkyScan microtomography and 3-point bending undertaken.
Muscle: WT mice had the greatest normalised grip strength at all ages. Mdx:utr had higher mean grip strength at 7 weeks than mdx mice. CK assay results indicated significantly higher serum values from mdx (P<0.02) and mdx:utr (P<0.002), versus WT. Muscle histology was consistent with these observations.
Growth: No significant difference in bodyweight gain between groups at any age and no difference in tail length by 7 weeks. Gain in body length was 0.3 mm less/day when comparing the mdx and mdx:utr to WT mice culled at 7 weeks, but Micro-CT of tibial length revealed no genotype difference.
Bone: No significant differences in trabecular bone parameters between groups at any age, except for structural model index (greater in 3-week WT mice, P<0.04). Cortical bone parameters and bone mechanical properties similar at all ages. There are very limited strategies available to treat short stature and osteoporosis in DMD. We have demonstrated that young mdx and mdx:utr mice exhibit muscle weakness, but dont show a bone or growth phenotype and therefore have clear limitations. Finding a more suitable pre-clinical mouse model is therefore essential.
22 - 24 Nov 2017
British Society for Paediatric Endocrinology and Diabetes