source: Neuromuscular Disorders
C. Huchet, G. Toumaniantz, T. Larcher, B. Fraysse, A. Lafoux, S. Remy, D. Caudal, M. Allais, E. Amosse, I. Anegon, C. Le Guiner
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the gene encoding dystrophin. The evaluation of potential therapeutic products requires relevant animal models exhibiting a phenotype very close to those observed in human patients. If both large and small animal species deficient for dystrophin (especially mice and dogs) have been extensively used for preclinical studies of DMD, they present some limitations, including the absence or very delayed development of cardiomyopathy. We recently generated a line of dmd mutated-rats (Dmdmdx) using TALENs and initially characterized it at two stages of development. To complete this characterization, we performed a large natural history study, during which different groups of Dmdmdx rats and littermate wild-type controls were followed over several generations and exhaustively evaluated at different time points (1.5, 3, 4.5, 7, 10 and 12 months). One supplemental group of Dmdmdx rats was also used to document the lifespan, as well as the causes of death. We showed that life span of Dmdmdx rats is significantly reduced. Weight, blood biomarkers concentrations, muscle strength and fatigue measured by grip force test, muscle calcium homeostasis and histology (including quantification of fibrosis) in skeletal muscles, diaphragm and heart, are all significantly impaired as soon as the age of 1.5 months and show a clear stepwise evolution along with age. Moreover, echo and electrocardiography approaches highlighted a significant and rapid concentric remodeling associated to an alteration of diastolic function, which progressed unfavorably with age towards systolic heart failure with rhythm disorders. In conclusion, with systematic and stepwise aggressive phenotypes at both the muscular and the cardiac levels, similar to what occurs in DMD patients, this unique and newly developed Dmdmdx rat model is now one of the best animal models for the preclinical evaluations of new treatments for DMD.
Université de Nantes, France; Therassay Capacites, France
/10.1016/j.nmd.2017.06.546 read more