title: Superoxide release from contracting skeletal muscle in pulmonary TNF-α overexpression mice.
abstract: Chronic obstructive pulmonary disease (COPD) often results in increased levels of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, which circulates in the blood. However, it is not clear whether pulmonary TNF-α overexpression (a COPD mimic) induces excessive reactive oxygen species (ROS) formation in skeletal muscle and thereby may contribute to the muscle impairment often seen in COPD. We hypothesized that ROS generation in contracting skeletal muscle is elevated when there is TNF-α overproduction in the lung and that this can induce muscle dysfunction. Cytochrome c (cyt c) in the perfusate was used to assay superoxide (O2(·-)) release from isolated contracting soleus muscles from transgenic mice of pulmonary TNF-α overexpression (Tg(+)) and wild-type (WT) mice. Our results showed that Tg(+) muscle released significantly higher levels of O2(·-) than WT during a period of intense contractile activity (in nmol/mg wt; 17.5 ± 2.3 vs. 4.4 ± 1.3, respectively; n = 5; P < 0.05). In addition, the soleus muscle demonstrated a significantly reduced fatigue resistance in Tg(+) mice compared with WT mice. Perfusion of the contracting soleus muscle with superoxide dismutase, which specifically scavenges O2(·-) in the perfusate, resulted in significantly less cyt c reduction, thereby indicating that the type of ROS released from the Tg(+) muscles is O2(·-). Our results demonstrate that pulmonary TNF-α overexpression leads to a greater O2(·-) release from contracting soleus muscle in Tg(+) compared with WT and that the excessive formation of O2(·-) in the contracting muscle of Tg(+) mice leads to earlier fatigue.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California;
authors.forename: Li
authors.initials: L
authors.lastname: Zuo
authors.forename: Allison H
authors.initials: AH
authors.lastname: Hallman
authors.forename: William J
authors.initials: WJ
authors.lastname: Roberts
authors.forename: Peter D
authors.initials: PD
authors.lastname: Wagner
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hogan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D013482:Superoxide Dismutase
keywords: cytochrome c; fatigue; reactive oxygen species; superoxide dismutase