Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

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.

IL-34 is a Treg-specific cytokine and mediates transplant tolerance

“…The concentration of the anti-IL-34 Ab was in a relatively high range, but we cannot exclude that the affinity of this Ab is not optimal, and the adequate isotype-and species-negative control validates this observation. The generation of IL-34-deficient rats using engineered nucleases as previously done in our laboratory (45,46) is under way and will help to further address the key role of IL-34 in Treg function. Similarly, the generation of FOXP3-GFP rats will help to define whether FOXP3 + Tregs are the only Tregs that express IL-34 and to further explore the role of IL-34 in Treg biology.…”

The Pathogenesis and Therapy of Muscular Dystrophies

“…Furthermore, the availability of internationally accepted protocols for the mdx mouse [see the TREAT-NMD (Translational Research in Europe-Assessment and Treatment of Neuromuscular Diseases) website at http://www.treat-nmd.eu] is an invaluable resource in DMD research. Larcher et al (136) recently described a promising Dmd mutated rat model with phenotypic properties close to the human DMD pathology. Rats are a convenient size and allow behavioral experiments and studies with high statistical power.…”

The advances and challenges of Gene Therapy for Duchenne Muscular Dystrophy

“…Another model of dystrophic rat produced with TALENs by deleting exon 23, also showed a severe phenotype as the animal advanced in age. The presence of ibrosis and the in iltration of adipose tissue in certain skeletal muscles has been noted [122]. This is model, which is not too expensive, that can be used to replace the mdx mouse.…”