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.

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Chronic obstructive pulmonary disease (COPD) commonly results in elevated levels of tumor necrosis factor‐alpha (TNF‐α). However, the mechanism of extracellular reactive oxygen species (ROS) formation in skeletal muscle isolated from pulmonary TNF‐α overexpression mice, has been overlooked. We hypothesized that ROS can be released from contracting skeletal muscle when there is increased TNF‐α formation in the lung and that this causes muscle early fatigue. Using wild type (WT) and pulmonary TNF‐α overexpression mice (Tg+), we performed a cytochrome c (cyt c) assay to measure extracellular superoxide (O2•–, one of the major types of ROS) production in isolated contracting soleus muscle. Our results showed that Tg+ soleus released higher levels of O2•– than WT during the contraction period (n = 5; P < 0.05). Tg+ soleus muscle also presented a reduced fatigue resistance compared to WT muscle. Perfusion of the contracting soleus with membrane‐impermeable superoxide dismutase, an extracellular O2•– scavenger, resulted in less cyt c reduction confirming that the type of ROS released from the Tg+ muscles was O2•–. We conclude that TNF‐α overexpression in the lung induces more O2•– release from Tg+ than WT muscle, and that the extracellular formation of O2•– markedly reduces the fatigue resistance in the Tg+ muscle. Thus, this study highlights O2•– as a potential mechanistic mediator in COPD induced muscle impairment. Grant Funding Source: Supported by NHLBI Grant PPG‐HL‐091830, NIAMS Grant AR040155, OSU‐HRS 013000