Journal
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
Volume 306, Issue 1, Pages R75-R81Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00425.2013
Keywords
reactive oxygen species; superoxide dismutase; cytochrome c; fatigue
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Funding
- National Heart, Lung, and Blood Institute [PPG-HL-091830]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR040155]
- Oakland University General Fund [G110]
- Oakland University Research Excellence Fund of Biomedical Research
- Ohio State University Health Rehabilitation Sciences Fund [013000]
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Chronic obstructive pulmonary disease (COPD) often results in increased levels of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, which circulates in the blood. However, it is not clear whether pulmonary TNF-alpha 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-alpha overproduction in the lung and that this can induce muscle dysfunction. Cytochrome c (cyt c) in the perfusate was used to assay superoxide (O-2(.-)) release from isolated contracting soleus muscles from transgenic mice of pulmonary TNF-alpha overexpression (Tg(+)) and wild-type (WT) mice. Our results showed that Tg similar to muscle released significantly higher levels of O-2 similar to 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 O-2(.-) in the perfusate, resulted in significantly less cyt c reduction, thereby indicating that the type of ROS released from the Tg(+) muscles is O-2(.-). Our results demonstrate that pulmonary TNF-alpha overexpression leads to a greater O-2(.-) release from contracting soleus muscle in Tg(+) compared with WT and that the excessive formation of O-2(.-) in the contracting muscle of Tg(+) mice leads to earlier fatigue.
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