title: Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice.
abstract: Reactive oxygen species (ROS) have been widely implicated in the pathogenesis of diabetes and more recently in mitochondrial alterations in skeletal muscle of diabetic mice. However, so far the exact sources of ROS in skeletal muscle have remained elusive. Aiming at better understanding the causes of mitochondrial alterations in diabetic muscle, we designed this study to characterize the sites of ROS production in skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Hyperglycemic STZ mice showed increased markers of systemic and muscular oxidative stress, as evidenced by increased circulating H(2)O(2) and muscle carbonylated protein levels. Interestingly, insulin treatment reduced hyperglycemia and improved systemic and muscular oxidative stress in STZ mice. We demonstrated that increased oxidative stress in muscle of STZ mice is associated with an increase of xanthine oxidase (XO) expression and activity and is mediated by an induction of H(2)O(2) production by both mitochondria and XO. Finally, treatment of STZ mice, as well as high-fat and high-sucrose diet-fed mice, with oxypurinol reduced markers of systemic and muscular oxidative stress and prevented structural and functional mitochondrial alterations, confirming the in vivo relevance of XO in ROS production in diabetic mice. These data indicate that mitochondria and XO are the major sources of hyperglycemia-induced ROS production in skeletal muscle and that the inhibition of XO reduces oxidative stress and improves mitochondrial alterations in diabetic muscle.
authors.affiliation: UMR INSERM U870/INRA U1235, Faculté de médecine Lyon Sud, 165 chemin du grand Revoyet, Oullins Cedex.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bravard
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bonnard
authors.forename: Annie
authors.initials: A
authors.lastname: Durand
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Chauvin
authors.forename: Roland
authors.initials: R
authors.lastname: Favier
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010117:Oxypurinol / Q000494:pharmacology; D050050:Protein Carbonylation / Q000187:drug effects; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D007328:Insulin; D012313:RNA; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D010117:Oxypurinol