Résumé :
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LMNA gene encodes lamins A/C, ubiquitous proteins of the nuclear envelope. They play crucial role in maintaining nuclear shape and stiffness. If mutated, they lead to muscular and cardiac diseases maybe due, in part, to excessive mechanical stress sensitivity ("mechanical hypothesis"). The Emery-Dreifuss muscular dystrophy (EDMD) is a LMNA-related disorder. It associates muscular disease and dilated cardiomyopathy (DCM).To understand the pathophysiological mechanisms involved in a severe form of EDMD, we have deleted the lysine 32 in mouse Lmna gene. The aim of this study is to characterize the phenotype of the heterozygous (Het) mice LmnadelK32/+ and to investigate the sensitivity of myocardium to exercise.Het mice show a progressive cardiac contractile dysfunction, evolving in DCM which leads to death between 35 and 70 weeks of age.17 week-old Het and Wt mice were subjected to strenuous treadmill exercise for 5 weeks, 5 days/week, 1h/day at speed ranging from 27 to 35 cm.s-1. Before the running protocol, cardiac function of Het mice was similar to Wt-littermates. After 5 weeks, Het mice (trained (T) and sedentary (S)) showed decreased cardiac function compared to Wt mice (FS: 34±6,1% vs 40,4±4,7%) but cardiac function of Het-T did not differ from Het-S. There is no increase in heart-to-body weight ratio and expression level of cardiac remodelling markers ANF and BNP as well as cellular and nuclear size of cardiomyocytes are similar in Het-T and Het-S mice. However, b-MHC is 3-fold increased in Het vs Wt mice. All these parameters were not changed by training in Wt mice.In conclusion, the LmnaK32 mouse is the first mouse model harbouring a heterozygous Lmna gene mutation which develops a phenotype affecting specifically the heart. The pathophysiological mechanisms of the DCM are still unclear but contradicting with the "mechanical hypothesis", the heart of Het mice is not more vulnerable to exercise-induced mechanical stress than their Wt-littermates.
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