title: Delayed cardiomyopathy in dystrophin deficient mdx mice relies on intrinsic glutathione resource.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Institut Mondor de Recherche Biomédicale, Créteil, France.
authors.forename: Lara
authors.initials: L
authors.lastname: Khouzami
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Bourin
authors.forename: Christo
authors.initials: C
authors.lastname: Christov
authors.forename: Thibaud
authors.initials: T
authors.lastname: Damy
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Philippe
authors.initials: P
authors.lastname: Caramelle
authors.forename: Magali
authors.initials: M
authors.lastname: Perier
authors.forename: Karim
authors.initials: K
authors.lastname: Wahbi
authors.forename: Christophe
authors.initials: C
authors.lastname: Meune
authors.forename: Catherine
authors.initials: C
authors.lastname: Pavoine
authors.forename: Françoise
authors.initials: F
authors.lastname: Pecker
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D009202:Cardiomyopathies / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D005978:Glutathione / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D016189:Dystrophin; D005978:Glutathione