title: Inhibition of xanthine oxidase reduces oxidative stress and improves skeletal muscle function in response to electrically stimulated isometric contractions in aged mice.
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 (2.5mg/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.
authors.affiliation: Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Janna R
authors.initials: JR
authors.lastname: Jackson
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Hao
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Leonard
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Alway
mesh_terms: D000367:Age Factors; D000375:Aging; D000493:Allopurinol / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000096:biosynthesis; D002374:Catalase / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D005978:Glutathione / Q000096:biosynthesis; D005979:Glutathione Peroxidase / Q000096:biosynthesis; D006861:Hydrogen Peroxide / Q000378:metabolism; D007537:Isometric Contraction; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology*; D009142:Musculoskeletal Physiological Phenomena; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D019820:Xanthine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019820:Xanthine; D000493:Allopurinol; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D053148:Caspase 3; D005978:Glutathione