Abstract:
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Communication n° 279 Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early joint contractures, slowly progressive muscular wasting and weakness, and by adult age, development of cardiac conduction defects, arrhythmias, left ventricular dysfunction and dilation with heart failure. Autosomal dominant EDMD is caused by mutations in LMNA gene encoding lamins A/C, two components of the nuclear envelope. We developed a mouse model with a missense LMNA mutation (H222P) that was identified in a family with typical EDMD. These mice develop muscular dystrophy and dilated cardiomyopathy reminiscent of the human disease. Evaluation of cardiac function in the female LmnaH222P/H222P mice demonstrated cardiac dilation and systolic dysfunction already at 4 months of age. The severity of several chronic diseases, including chronic cardiomyopathies and muscular dystrophies, has been causally linked to an exacerbated production of the proinflammatory cytokine tumor necrosis factor alpha (TNF). We previously found that glutathione depletion was causally linked to high serum TNF levels and that therapeutic treatment with NAC, a glutathione precursor, prevented the TNF increase and preserved cardiac function in a model of failing rats. We now show that TNF is elevated in serum (x3), gastrocnemius (detectable vs undetectable) and heart (x7) of female LmnaH222P/H222P mice of 6-10 months of age, compared to wild type mice. TNF level elevation is associated with depletion in glutathione content in serum (-50%), gastrocnemius (-23%) and cardiac tissue (-30%). Further examination of the cardiac tissue shows oxidative stress, assessed by malondialdehyde levels, in LmnaH222P/H222P mice. One month of oral NAC treatment reverses oxidative stress, normalizes glutathione content and TNF level, and improves echo-cardiographic parameters of the heart function. This study suggests: 1) the contribution of TNF to the progression of the cardiac and muscular diseases in LmnaH222P/H222P mice; 2) the therapeutic potency of for the management of EDMD.
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