Disease course in mdx:utrophin+/- mice: comparison of three mouse models of Duchenne muscular dystrophy.

ABSTRACT

The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdxutrophin(-/-) (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdxutrophin(+/-) mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdxutrophin(+/-) mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdxutrophin(+/-), and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdxutrophin(+/-) mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdxutrophin(+/-) mice compared to mdx mice at 12 months. Mdxutrophin(+/-) mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdxutrophin(+/-) muscle compared to mdx at most ages examined. Generally, mdxutrophin(+/-) mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdxutrophin(+/-) mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus.