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.

Reactive oxygen species formation and bystander effects in gradient irradiation on human breast cancer cells

“…O 2 ·− and other relatively stable ROS, such as hydrogen peroxide (H 2 O 2 ) have been implicated in activation signaling pathways in neighboring cells by regulating stress-related proteins such as MAPK and p53 under low doses of irradiation exposure [27, 28]. The mechanism for the increase of extracellular O 2 ·− is complex and could be associated with an enhanced inflammatory response such as TNF-α overexpression [29]. Other ROS which are derived from O 2 ·− , such as H 2 O 2 , may cause damage towards the normal or less-irradiated cells by giving sufficient perfusion time, exacerbating bystander effects [18, 27, 30].…”

Cytokine Signaling in Skeletal Muscle Wasting

“…So the question is whether circulating or lung-derived TNF-/ would have an impact on muscle function. In a transgenic mouse model overexpressing TNF-/ in the lung, TNF-/ impaired peripheral skeletal muscle function due to excessive formation of superoxide in contracting skeletal muscle [36,37]. However, a study of 426 COPD patients over a 3-year period found that TNF-/ levels were associated with muscle loss only in patients who were cachectic at entry into the study; the authors concluded that inflammation is a consequence rather than a cause of initial loss of fat-free mass [38].…”

Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments

“…In addition, CS has been associated with elevated ROS production by leukocytes in the airways of both acute and chronic smokers (21). Subsequently, this production is stimulated by the release of ROS by neutrophils and macrophages, in conjunction with the inflammatory response (such as TNF-␣ production) to CS (78,146). Furthermore, excess CS-induced ROS cannot be neutralized by endogenous antioxidants, ultimately resulting in oxidative stress-induced damage (21), which has been frequently demonstrated in animal models.…”