Respiratory characterization of a humanized Duchenne muscular dystrophy mouse model

Respir Physiol Neurobiol. 2024 Aug:326:104282. doi: 10.1016/j.resp.2024.104282. Epub 2024 May 21.

Abstract

Duchenne muscular dystrophy (DMD) is the most common X-linked disease. DMD is caused by a lack of dystrophin, a critical structural protein in striated muscle. Dystrophin deficiency leads to inflammation, fibrosis, and muscle atrophy. Boys with DMD have progressive muscle weakness within the diaphragm that results in respiratory failure in the 2nd or 3rd decade of life. The most common DMD mouse model - the mdx mouse - is not sufficient for evaluating genetic medicines that specifically target the human DMD (hDMD) gene sequence. Therefore, a novel transgenic mouse carrying the hDMD gene with an exon 52 deletion was created (hDMDΔ52;mdx). We characterized the respiratory function and pathology in this model using whole body plethysmography, histology, and immunohistochemistry. At 6-months-old, hDMDΔ52;mdx mice have reduced maximal respiration, neuromuscular junction pathology, and fibrosis throughout the diaphragm, which worsens at 12-months-old. In conclusion, the hDMDΔ52;mdx exhibits moderate respiratory pathology, and serves as a relevant animal model to study the impact of novel genetic therapies, including gene editing, on respiratory function.

Keywords: Diaphragm; Duchenne; Fibrosis; Respiratory; Tongue.

MeSH terms

  • Animals
  • Diaphragm / pathology
  • Diaphragm / physiopathology
  • Disease Models, Animal*
  • Dystrophin / deficiency
  • Dystrophin / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Mice, Transgenic*
  • Muscular Dystrophy, Duchenne* / genetics
  • Muscular Dystrophy, Duchenne* / pathology
  • Muscular Dystrophy, Duchenne* / physiopathology
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Respiratory Insufficiency / etiology

Substances

  • Dystrophin
  • DMD protein, human