The existence of hypoxia-induced reactive oxygen species (ROS) production remains controversial. However, numerous observations with a variety of methods and in many cells and tissue types are supportive of this idea. Skeletal muscle appears to behave much like heart in that in the early stages of hypoxia there is a transient elevation in ROS, whereas in chronic exposure to very severe hypoxia there is evidence of ongoing oxidative stress. Important remaining questions that are addressed in this review include the following. Are there levels of Po₂in skeletal muscle, typical of physiological or mildly pathophysiological conditions, that are low enough to induce significant ROS production? Does the ROS associated with muscle contractile activity reflect imbalances in oxygen uptake and demand that drive the cell to a more reduced state? What are the possible molecular mechanisms by which ROS may be elevated in hypoxic skeletal muscle? Is the production of ROS in hypoxia of physiological significance, both with respect to cell signaling pathways promoting cell function and with respect to damaging effects of long-term exposure? Discussion of these and other topics leads to general conclusions that hypoxia-induced ROS may be a normal physiological response to imbalance in oxygen supply and demand or environmental stress and may play a yet undefined role in normal response mechanisms to these stimuli. However, in chronic and extreme hypoxic exposure, muscles may fail to maintain a normal redox homeostasis, resulting in cell injury or dysfunction.

Previous uncontrolled reports have suggested that HIV-seropositive persons develop an accelerated form of emphysema. To characterize the risk for emphysema in a stable HIV-seropositive outpatient population. Controlled, cross-sectional analysis. Midwestern urban community. HIV-seropositive persons (n = 114) without AIDS-related pulmonary complications and HIV-seronegative controls (n = 44), matched for age and smoking history. Measurement of pulmonary function, bronchoalveolar lavage, and high-resolution computed tomography of the chest. The incidence of emphysema was 15% (17 of 114) in the HIV-seropositive group compared with 2% (1 of 44) in the HIV-seronegative group (P = 0.025). The incidence of emphysema in participants with a smoking history of 12 pack-years or greater was 37% (14 of 38 persons) in the HIV-seropositive group compared with 0% (0 of 14 persons) in the HIV-seronegative group (P = 0.011). The percentage of cytotoxic lymphocytes in lavage fluid was much higher in HIV-seropositive smokers with emphysema. Infection with HIV accelerates the onset of smoking-induced emphysema. The results of this study support the emerging concept that cytotoxic lymphocytes may have an important role in emphysema pathogenesis.

Skeletal muscles are exposed to increased temperatures during intense exercise, particularly in high environmental temperatures. We hypothesized that heat may directly stimulate the reactive oxygen species (ROS) formation in diaphragm (one kind of skeletal muscle) and thus potentially play a role in contractile and metabolic activity. Laser scan confocal microscopy was used to study the conversion of hydroethidine (a probe for intracellular ROS) to ethidium (ET) in mouse diaphragm. During a 30-min period, heat (42°C) increased ET fluorescence by 24 ± 4%, whereas in control (37°C), fluorescence decreased by 8 ± 1% compared with baseline ( P < 0.001). The superoxide scavenger Tiron (10 mM) abolished the rise in intracellular fluorescence, whereas extracellular superoxide dismutase (SOD; 5,000 U/ml) had no significant effect. Reduction of oxidized cytochrome c was used to detect extracellular ROS in rat diaphragm. After 45 min, 53 ± 7 nmol cytochrome c · g dry wt⁻¹ · ml⁻¹ were reduced in heat compared with 22 ± 13 nmol · g⁻¹ · ml⁻¹ in controls ( P < 0.001). SOD decreased cytochrome creduction in heat to control levels. The results suggest that heat stress stimulates intracellular and extracellular superoxide production, which may contribute to the physiological responses to severe exercise or the pathology of heat shock.

Superoxide anion radical (O₂^•−) is released from skeletal muscle at rest and is particularly elevated during conditions of heat stress (42°C). Previous studies have shown that in isolated rat diaphragm O₂^•−release is not dependent on mitochondrial electron transport, reduced NADP oxidase activity, or the integrity of membrane anion channels. This study hypothesized that O₂^•−release, as measured by cytochrome c reduction, is linked to metabolism of arachidonic acid. Phospholipase A₂inhibition with manoalide significantly decreased O₂^•−release. In downstream pathways, neither the blockage of cyclooxygenase with indomethacin nor the inhibition of cytochrome P-450-dependent monooxygenase with SKF-525A decreased O₂^•−release. However, lipoxygenase (LOX) inhibition with general LOX blockers 5,8,11,14-eicosatetraynoic acid and cinnamyl-3,4-dihydroxy-α-cyanocinnamate greatly attenuated the signal. Furthermore, the specific 5-LOX inhibitor diethylcarbamazine also significantly decreased O₂^•−release. Immunohistochemistry localized 5- and 12-LOX to the cytosol and sarcolemma of muscle cells. Confocal studies, using the O₂^•−-sensitive fluorescent indicator hydroethidine, demonstrated that LOX inhibition had no significant influence on intracellular O₂^•−formation. When compared with the cytochrome c results, this indicates that intra- and extracellular O₂^•−must arise from different sources. These data show for the first time that arachidonic acid metabolism through LOX activity, is a major source of extracellular O₂^•−release in skeletal muscle.

Lung volumes and inspiratory muscle (IM) function tests were measured in 16 competitive female swimmers (age 19 +/- 1 yr) before and after 12 wk of swim training. Eight underwent additional IM training; the remaining eight were controls. Vital capacity (VC) increased 0.25 +/- 0.25 liters (P less than 0.01), functional residual capacity (FRC) increased 0.39 +/- 0.29 liters (P less than 0.001), and total lung capacity (TLC) increased 0.35 +/- 0.47 (P less than 0.025) in swimmers, irrespective of IM training. Residual volume (RV) did not change. Maximum inspiratory mouth pressure (PImax) measured at FRC changed -43 +/- 18 cmH2O (P less than 0.005) in swimmers undergoing IM conditioning and -29 +/- 25 (P less than 0.05) in controls. The time that 65% of prestudy PImax could be endured increased in IM trainers (P less than 0.001) and controls (P less than 0.05). All results were compared with similar IM training in normal females (age 21.1 +/- 0.8 yr) in which significant increases in PImax and endurance were observed in IM trainers only with no changes in VC, FRC, or TLC (Clanton et al., Chest 87: 62–66, 1985). We conclude that 1) swim training in mature females increases VC, TLC, and FRC with no effect on RV, and 2) swim training increases IM strength and endurance measured near FRC.