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Inhibition of xanthine oxidase reduces oxidative stress and improves skeletal muscle function in response to electrically stimulated isometric contractions in aged mice
Authors:Ryan Michael J  Jackson Janna R  Hao Yanlei  Leonard Stephen S  Alway Stephen E
Institution:
  • a Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV 26506, USA
  • b Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, WV 26506, USA
  • c Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV 26506, USA
  • d Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26506, USA
  • Abstract:Oxidative stress is a putative factor responsible for reducing function and increasing apoptotic signaling in skeletal muscle with aging. This study examined the contribution and functional significance of the xanthine oxidase enzyme as a potential source of oxidant production in aged skeletal muscle during repetitive in situ electrically stimulated isometric contractions. Xanthine oxidase activity was inhibited in young adult and aged mice via a subcutaneously placed time-release (2.5 mg/day) allopurinol pellet, 7 days before the start of in situ electrically stimulated isometric contractions. Gastrocnemius muscles were electrically activated with 20 maximal contractions for 3 consecutive days. Xanthine oxidase activity was 65% greater in the gastrocnemius muscle of aged mice compared to young mice. Xanthine oxidase activity also increased after in situ electrically stimulated isometric contractions in muscles from both young (33%) and aged (28%) mice, relative to contralateral noncontracted muscles. Allopurinol attenuated the exercise-induced increase in oxidative stress, but it did not affect the elevated basal level of oxidative stress that was associated with aging. In addition, inhibition of xanthine oxidase activity decreased caspase-3 activity, but it had no effect on other markers of mitochondrial-associated apoptosis. Our results show that compared to control conditions, suppression of xanthine oxidase activity by allopurinol reduced xanthine oxidase activity, H2O2 levels, lipid peroxidation, and caspase-3 activity; prevented the in situ electrically stimulated isometric contraction-induced loss of glutathione; prevented the increase in catalase and copper-zinc superoxide dismutase activities; and increased maximal isometric force in the plantar flexor muscles of aged mice after repetitive electrically evoked contractions.
    Keywords:AIF  apoptosis-inducing factor  Apaf-1  apoptosis peptidase-activating factor 1  Bax  Bcl-2-associated X protein  Bcl-2  B cell leukemia/lymphoma-2  CuZnSOD  copper-zinc superoxide dismutase  GPx  glutathione peroxidase  GSH  reduced glutathione  GSSG  oxidized glutathione  HAE  4-hydroxyalkenal  MDA  malondialdehyde  MnSOD  mitochondrial manganese superoxide dismutase  NF-κB  nuclear factor κB  NFM  nonfat milk protein  RFU  relative fluorescence units  TBS-T  Tris-buffered saline with 0  05% Tween 20
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