Thibaut Larcher 1 , Aude Lafoux 2 , Laurent Tesson 3 , Séverine Remy 3 , Virginie Thepenier 3 , Virginie François 4 , Caroline Le Guiner 4 , 5 , Helicia Goubin 1 , Maéva Dutilleul 1 , Lydie Guigand 1 , Gilles Toumaniantz 2 , Anne De Cian 6 , Charlotte Boix 6 , Jean-Baptiste Renaud 6 , Yan Cherel 1 , Carine Giovannangeli 6 , Jean-Paul Concordet 6 , Ignacio Anegon 3 , * , Corinne Huchet 2 , *
13 October 2014
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 ( Dmd mdx ) 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 Dmd mdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmd mdx 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, Dmd mdx rats represent a new faithful small animal model of DMD.