Oxidative stress and Nrf2 signaling in McArdle disease

• Published in: Molecular genetics and metabolism Vol. 110; no. 3; pp. 297 - 302
• Main Authors: Kitaoka, Yu, Ogborn, Daniel I., Nilsson, Mats I., Mocellin, Nicholas J., MacNeil, Lauren G., Tarnopolsky, Mark A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013
• Subjects: Aldehydes - metabolism; Female; Gene Expression Regulation; Glucosyltransferases - metabolism; Glycogen Storage Disease Type V - genetics; Glycogen Storage Disease Type V - metabolism; Heme Oxygenase-1 - metabolism; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Kelch-Like ECH-Associated Protein 1; Male; McArdle disease; Middle Aged; Mitochondria - metabolism; NAD(P)H Dehydrogenase (Quinone) - metabolism; NF-E2-Related Factor 2 - metabolism; Nuclear factor erythroid 2-related factor 2; Oxidative stress; Oxidative Stress - genetics; Signal Transduction; Transcription, Genetic; Uric Acid - blood; NQO1; Oxidative stress; AMP; McArdle disease; PYGM; ADP; GPX; Nuclear factor erythroid 2-related factor 2; GCLC; ARE; TXNRD; Nrf2; MD; Keap1; HMOX1; GCLM; ATP; γ-glutamylcysteine ligase regulatory subunit; thioredoxin reductase; muscle glycogen phosphorylase; NAD(P)H quinone oxidoreductase 1; adenosine diphosphate; antioxidant response element; heme oxygenase 1; Kelch-like ECH-associated protein 1; adenosine monophosphate; adenosine triphosphate; γ-glutamylcysteine ligase catalytic subunit; glutathione peroxidase
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2013.06.022

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. •Patients with McArdle disease (MD) have elevated muscle protein carbonyls and 4-hydroxynonenal in comparison with healthy, age and activity matched controls.•Nuclear abundance of Nrf2 and Nrf2-antioxidant response element (ARE) binding was higher in MD patients compared with 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.