title: Effect of xanthine oxidase-generated extracellular superoxide on skeletal muscle force generation.
abstract: Skeletal muscle contractions increase superoxide anion in skeletal muscle extracellular space. We tested the hypotheses that 1) after an isometric contraction protocol, xanthine oxidase (XO) activity is a source of superoxide anion in the extracellular space of skeletal muscle and 2) the increase in XO-derived extracellular superoxide anion during contractions affects skeletal muscle contractile function. Superoxide anion was monitored in the extracellular space of mouse gastrocnemius muscles by following the reduction of cytochrome c in muscle microdialysates. A 15-min protocol of nondamaging isometric contractions increased the reduction of cytochrome c in microdialysates, indicating an increase in superoxide anion. Mice treated with the XO inhibitor oxypurinol showed a smaller increase in superoxide anions in muscle microdialysates following contractions than in microdialysates from muscles of vehicle-treated mice. Intact extensor digitorum longus (EDL) and soleus muscles from mice were also incubated in vitro with oxypurinol or polyethylene glycol-tagged Cu,Zn-SOD. Oxypurinol decreased the maximum tetanic force produced by EDL and soleus muscles, and polyethylene glycol-tagged Cu,Zn-SOD decreased the maximum force production by the EDL muscles. Neither agent influenced the rate of decline in force production when EDL or soleus muscles were repeatedly electrically stimulated using a 5-min fatiguing protocol (stimulation at 40 Hz for 0.1 s every 5 s). Thus these studies indicate that XO activity contributes to the increased superoxide anion detected within the extracellular space of skeletal muscles during nondamaging contractile activity and that XO-derived superoxide anion or derivatives of this radical have a positive effect on muscle force generation during isometric contractions of mouse skeletal muscles.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: M C
authors.initials: MC
authors.lastname: Gomez-Cabrera
authors.forename: G L
authors.initials: GL
authors.lastname: Close
authors.forename: A
authors.initials: A
authors.lastname: Kayani
authors.forename: A
authors.initials: A
authors.lastname: McArdle
authors.forename: J
authors.initials: J
authors.lastname: Viña
authors.forename: M J
authors.initials: MJ
authors.lastname: Jackson
mesh_terms: D000818:Animals; D045304:Cytochromes c / Q000378:metabolism; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism*; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018763:Muscle Fatigue / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D010117:Oxypurinol / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D013481:Superoxides; D045304:Cytochromes c; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D010117:Oxypurinol