title: Oxidative stress and Nrf2 signaling in McArdle disease.
abstract: McArdle disease (MD) is a metabolic myopathy due to myophosphorylase deficiency, which leads to a severe limitation in the rate of adenosine triphosphate (ATP) resynthesis. Compensatory flux through the myoadenylate deaminase > > xanthine oxidase pathway should result in higher oxidative stress in skeletal muscle; however, oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2) mediated antioxidant response cascade in MD patients have not yet been examined. We show that MD patients have elevated muscle protein carbonyls and 4-hydroxynonenal (4-HNE) in comparison with healthy, age and activity matched controls (P < 0.05). Nuclear abundance of Nrf2 and Nrf2-antioxidant response element (ARE) binding was also higher in MD patients compared with controls (P < 0.05). The expressions of Nrf2 target genes were also higher in MD patients vs. controls. These observations suggest that MD patients experience elevated levels of oxidative stress, and that the Nrf2-mediated antioxidant response cascade is up-regulated in skeletal muscle to compensate.
authors.affiliation: Departments of Pediatrics and Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario, L8N 3Z5 Canada. Electronic address: kitaoka@mcmaster.ca.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kitaoka
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Ogborn
authors.forename: Mats I
authors.initials: MI
authors.lastname: Nilsson
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Mocellin
authors.forename: Lauren G
authors.initials: LG
authors.lastname: MacNeil
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005964:Glucosyltransferases / Q000378:metabolism; D006012:Glycogen Storage Disease Type V / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D014527:Uric Acid / Q000097:blood
chemical_list: D000447:Aldehydes; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D014527:Uric Acid; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005964:Glucosyltransferases; C027576:4-hydroxy-2-nonenal
keywords: ADP; AMP; ARE; ATP; GCLC; GCLM; GPX; HMOX1; Keap1; Kelch-like ECH-associated protein 1; MD; McArdle disease; NAD(P)H quinone oxidoreductase 1; NQO1; Nrf2; Nuclear factor erythroid 2-related factor 2; Oxidative stress; PYGM; TXNRD; adenosine diphosphate; adenosine monophosphate; adenosine triphosphate; antioxidant response element; glutathione peroxidase; heme oxygenase 1; muscle glycogen phosphorylase; nuclear factor erythroid 2-related factor 2; thioredoxin reductase; γ-glutamylcysteine ligase catalytic subunit; γ-glutamylcysteine ligase regulatory subunit