In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.
Irisin is mainly released from skeletal muscle (myocytes) and promotes thermogenesis by browning of the white adipose tissue. Although exercise has been shown to increase irisin concentration in blood and myocytes via up-regulation peroxisome proliferator receptor γ coactivator-1α (PGC-1α) expression, the influence of exercise intensity on irisin secretion remains unclear. Therefore, we determined circulating irisin responses following a single bout of running at different intensities. Six sedentary males underwent treadmill running under two different conditions: a low-intensity (40% of V 4 O 2max ) exercise trial (LIE) or a high-intensity (80% of V 4 O 2max ) exercise trial (HIE). The exercises in LIE and HIE were lasted for 20 and 40 min, respectively. All subjects underwent the two trials on separate days, and a randomized cross-over design was used. Blood samples were collected before (Pre) and immediately after exercise, at 3, 6, and 19 h after exercise. Energy consumption during exercise did not significantly differ between the two trials. HIE significantly increased blood lactate and serum lactate dehydrogenase levels (P < 0.05). Compared with pre-exercise levels, the irisin concentrations were elevated at 6 h (18% increase) and 19 h (23% increase) after HIE, but significantly decreased after LIE. The relative irisin concentrations (compared with pre-exercise levels) were significantly greater in HIE than in LIE immediately after exercise, and at 6 and 19 h after exercise (P < 0.05). These findings suggest that irisin secretion after acute running exercise is affected by exercise intensity, independent of energy consumption.
LJ. Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway. Am J Physiol Endocrinol Metab 294: E889-E897, 2008. First published February 26, 2008 doi:10.1152/ajpendo.00150.2007.-We determined the acute effects of oxidative stress on glucose uptake and intracellular signaling in skeletal muscle by incubating muscles with reactive oxygen species (ROS). Xanthine oxidase (XO) is a superoxide-generating enzyme that increases ROS. Exposure of isolated rat extensor digitorum longus (EDL) muscles to Hx/XO (Hx/XO) for 20 min resulted in a dose-dependent increase in glucose uptake. To determine whether the mechanism leading to Hx/XO-stimulated glucose uptake is associated with the production of H2O2, EDL muscles from rats were preincubated with the H2O2 scavenger catalase or the superoxide scavenger superoxide dismutase (SOD) prior to incubation with Hx/XO. Catalase treatment, but not SOD, completely inhibited the increase in Hx/XO-stimulated 2-deoxyglucose (2-DG) uptake, suggesting that H2O2 is an intermediary leading to Hx/XO-stimulated glucose uptake with incubation. Direct H2O2 also resulted in a dose-dependent increase in 2-DG uptake in isolated EDL muscles, and the maximal increase was threefold over basal levels at a concentration of 600 mol/l H2O2. H2O2-stimulated 2-DG uptake was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, but not the nitric oxide inhibitor N G -monomethyl-L-arginine. H2O2 stimulated the phosphorylation of Akt Ser 473 (7-fold) and Thr 308 (2-fold) in isolated EDL muscles. H2O2 at 600 mol/l had no effect on ATP concentrations and did not increase the activities of either the ␣1 or ␣2 catalytic isoforms of AMP-activated protein kinase. These results demonstrate that acute exposure of muscle to ROS is a potent stimulator of skeletal muscle glucose uptake and that this occurs through a PI3K-dependent mechanism.
The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6C hi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.
The aim of this study was to examine whether xanthine oxidase (XOD)-derived hepatic oxidative damage occurs in the main not during but following strenuous exercise. The degree of damage to hepatic tissue catalyzed by XOD was investigated immediately and 3 h after a single bout of exhausting exercise, in allopurinol and saline injected female Wistar rats. Allopurinol treatment resulted in increased hypoxanthine and decreased uric acid contents in the liver compared with the saline treated group, immediately and 3 h after the exercise. Analysis immediately after the exercise showed no changes in hepatic hypoxanthine, uric acid, and thiobarbituric acid-reactive substance (TBARS) contents in the saline treated group, when compared with the resting controls. However, significant increases in uric acid contents in the saline treated livers were observed 3 h after the exercise, relative to the controls. Hepatic TBARS content in the saline treated group were markedly greater than those in both the control and allopurinol treated groups after 3 h of recovery following the exercise. It was concluded that a single bout of exhausting exercise may impose XOD-derived hepatic oxidative damage, primarily during the recovery phase after acute severe exercise.
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