Delayed cardiomyopathy in dystrophin deficient mdx mice relies on intrinsic glutathione resource. - Archive ouverte HAL Access content directly
Journal Articles American Journal of Pathology Year : 2010

Delayed cardiomyopathy in dystrophin deficient mdx mice relies on intrinsic glutathione resource.

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Abstract

Oxidative stress contributes to the pathogenesis of Duchenne muscular dystrophy (DMD). Although they have been a model for DMD, mdx mice exhibit slowly developing cardiomyopathy. We hypothesized that disease process was delayed owing to the development of an adaptive mechanism against oxidative stress, involving glutathione synthesis. At 15 to 20 weeks of age, mdx mice displayed a 33% increase in blood glutathione levels compared with age-matched C57BL/6 mice. In contrast, cardiac glutathione content was similar in mdx and C57BL/6 mice as a result of the balanced increased expression of glutamate cysteine ligase catalytic and regulatory subunits ensuring glutathione synthesis in the mdx mouse heart, as well as increased glutathione peroxidase-1 using glutathione. Oral administration from 10 weeks of age of the glutamate cysteine ligase inhibitor, l-buthionine(S,R)-sulfoximine (BSO, 5 mmol/L), led to a 33% and 50% drop in blood and cardiac glutathione, respectively, in 15- to 20-week-old mdx mice. Moreover, 20-week-old BSO-treated mdx mice displayed left ventricular hypertrophy associated with diastolic dysfunction, discontinuities in beta-dystroglycan expression, micronecrosis and microangiopathic injuries. Examination of the glutathione status in four DMD patients showed that three displayed systemic glutathione deficiency as well. In conclusion, low glutathione resource hastens the onset of cardiomyopathy linked to a defect in dystrophin in mdx mice. This is relevant to the glutathione deficiency that DMD patients may suffer.
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Dates and versions

inserm-00523117 , version 1 (04-10-2010)

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Lara Khouzami, Marie-Claude Bourin, Christo Christov, Thibaud Damy, Brigitte Escoubet, et al.. Delayed cardiomyopathy in dystrophin deficient mdx mice relies on intrinsic glutathione resource.: Glutathione resource in mdx mice. American Journal of Pathology, 2010, 177 (3), pp.1356-64. ⟨10.2353/ajpath.2010.090479⟩. ⟨inserm-00523117⟩
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