Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy

PLoS One. 2014 Oct 13;9(10):e110371. doi: 10.1371/journal.pone.0110371. eCollection 2014.

Abstract

A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Creatine Kinase / blood
  • Disease Models, Animal*
  • Dystrophin / deficiency*
  • Dystrophin / genetics
  • Dystrophin / metabolism
  • Exons
  • Female
  • Fibrosis
  • Gene Deletion
  • Gene Expression
  • Gene Targeting
  • Male
  • Muscle Weakness / genetics
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Animal*
  • Muscular Dystrophy, Duchenne / genetics*
  • Muscular Dystrophy, Duchenne / metabolism
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / physiopathology
  • Mutation
  • Myocardium / metabolism
  • Myocardium / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Ventricular Remodeling / genetics

Substances

  • Dystrophin
  • RNA, Messenger
  • Creatine Kinase

Grant support

Funding was provided by Région Pays de la Loire through Biogenouest, IBiSA program, Fondation Progreffe and TEFOR (Infrastructures d’Avenir of the French goverment), and the integrative genomic facility of Nantes for sequencing experiments. The authors thank the Wolfson Centre for Inherited Neuromuscular Disease for kindly supplying dystrophin monoclonal antibody. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.