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ABSTRACT: The following article from The Journal of Physiology, 'Exercise induces interleukin-8 expression in human skeletal muscle', by Thorbjorn CA Akerstrom, Adam Steensberg, Pernille Keller, Charlotte Keller, Milena Penkowa and Bente Klarlund Pedersen, published in The Journal of Physiology 563(2): 507-516, and online ahead of print on 23 December 2004 (doi:10.1113/jphysiol.2004.077610), has been retracted by agreement between Thorbjorn CA Akerstrom, Adam Steensberg, Pernille Keller, Charlotte Keller, Bente Klarlund Pedersen, the Editor-in-Chief, David J. Paterson, and Blackwell Publishing Ltd.
The Journal of Physiology 06/2011; · 4.72 Impact Factor
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ABSTRACT: The objective of this study was to use a novel and non-invasive model to explore whether: (1) exercise-induced increases in systemic levels of interleukin-6 (IL-6) and other cytokines can be ascribed to local production in working muscle; and (2) how acute release of retained blood from an exercised limb impacts on metabolites in the systemic circulation. On two experimental days, at least 3 weeks apart, six healthy moderately trained male subjects performed one-legged knee-extensor exercise for 2 h at 60% of their maximal workload. On one occasion venous outflow from the exercised leg was inhibited for 18 min by inflating a cuff around the thigh as proximally as possible immediately following exercise. On the control occasion venous outflow was not inhibited. Venous blood samples were collected from an arm vein at 2-min intervals after exercise. During inhibition of venous outflow from the exercised leg systemic plasma levels of IL-6 decreased within minutes to near pre-exercise levels, whereas plasma glucose levels increased to higher levels than without the cuff. After release of the cuff, systemic levels of IL-6 increased rapidly to match levels on the control occasion. On release of the cuff, plasma levels of free fatty acids (FFAs) declined more than without the cuff. In conclusion, the observed increase in systemic IL-6 plasma concentrations during exercise can be attributed to release from the working limb. Other potential sources of IL-6 outside the working limb do not contribute significantly to the increase in plasma IL-6 levels during exercise.
Arbeitsphysiologie 12/2010; 111(7):1351-9. · 2.15 Impact Factor
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ABSTRACT: IL-6 is a key modulator of immune function and suggested to be involved in skeletal muscle wasting as seen in sepsis.
Our objective was to determine the role of IL-6 in human in vivo systemic and skeletal muscle amino acid metabolism and protein turnover.
There were 12 healthy men infused for 3 h with saline (saline, n = 6) or recombinant human IL (rhIL)-6 (n = 6). Systemic and muscle protein turnover was determined with a combination of tracer dilution methodology, primed constant infusion of L-[ring-(2)H(5)]phenylalanine, and femoral arterial-venous blood differences and m. vastus lateralis biopsies after 2-h basal, 3-h infusion, and 3 h after infusion.
The IL-6 concentration after 30-min infusion was approximately 4 (saline) and 140 pg/ml (rhIL-6). Three-hour rhIL-6 infusion caused an approximate 50% decrease in muscle protein turnover, albeit synthesis was more suppressed than breakdown, causing a small increase in net muscle protein breakdown. Furthermore, rhIL-6 decreased arterial amino acid concentration with 20-40%, despite the increase net release from muscle.
We demonstrated that IL-6 profoundly alters amino acid turnover. A substantial decrease in plasma amino acids was observed with a concomitant 50% decrease in muscle protein turnover, however, modest increase in net muscle degradation. We hypothesize that the profound reduction in muscle protein turnover and modest increase in net degradation are primarily caused by the reduced plasma amino acid availability and not directly mediated by IL-6.
Journal of Clinical Endocrinology & Metabolism 08/2008; 93(7):2851-8. · 6.50 Impact Factor
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ABSTRACT: Previous studies have described the magnitude and time course by which several genes are regulated within exercising skeletal muscle. These include interleukin-6 (IL-6), interleukin-8 (IL-8), heme oxygenase-1 (HO-1), and heat shock protein-72 (HSP72), which are involved in secondary signaling and preservation of intracellular environment. However, the primary signaling mechanisms coupling contraction to transcription are unknown. We hypothesized that exercise-induced nitric oxide (NO) production is an important signaling event for IL-6, IL-8, HO-1, and HSP72 expression in muscle. Twenty healthy males participated in the study. By real-time PCR, mRNA levels for 11 genes were determined in thigh muscle biopsies obtained 1) before and after 2 h knee extensor exercise without (control) and with concomitant NO synthase inhibition (nitro-L-arginine methyl ester, L-NAME, 5 mg x kg(-1)); or 2) before and after 2 h femoral artery infusion of the NO donor nitroglycerin (NTG, 1.5 microg x kg(-1) x min(-1)). L-NAME caused marked reductions in exercise-induced expression of 4 of 11 mRNAs including IL-6, IL-8, and HO-1. IL-6 protein release from the study leg to the circulation increased in the control but not in the L-NAME trial. NTG infusion significantly augmented expression of the mRNAs attenuated by L-NAME. These findings advance the novel concept that NO production contributes to regulation of gene expression in muscle during exercise. Subsequently, we sought evidence for involvement of AMP-activated kinase or nuclear factor kappa B, but found none.
The FASEB Journal 10/2007; 21(11):2683-94. · 5.71 Impact Factor
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ABSTRACT: During exercise the concentration of interleukin (IL)-6 and of heat shock protein (HSP) 72 increases in plasma, especially in fasting subjects. Both IL-6 and HSP72 are involved in a variety of metabolic and immunological processes, including some within the central nervous system and, accordingly, they are present not only in plasma but also in the cerebrospinal fluid (CSF). To evaluate whether, the two pools equilibrate we determined the levels of IL-6 and HSP72 in CSF, at a time when their plasma levels were increased due to exercise. Measurements of TNF-alpha served as a control, as its plasma level remains stable during exercise. Two groups of healthy, fit males performed 2 h of strenuous exercise with either carbohydrate ingestion (n=8) or placebo (n=8). The concentration of IL-6, HSP72, and TNF-alpha was measured in arterial blood and in the CSF obtained by a lumbar puncture immediately after exercise. A third group of subjects served as resting controls (n=8). At rest, CSF levels of IL-6 and HSP72 were 2- and 3-fold higher than the plasma levels, respectively (P<.05). During exercise, with and without carbohydrate ingestion, plasma IL-6 increased 8- and 18-fold, respectively, and HSP72 increased 5-fold (P<.05). However, the concentrations of IL-6 and HSP72 in CSF did not change with exercise and were therefore below their corresponding plasma levels. The concentration of TNF-alpha in CSF was below that in plasma and both remained stable during exercise. The findings that resting CSF levels of IL-6 and HSP72 are higher than in plasma and that they remain stable despite exercise-induced, profound increases in their systemic levels, suggest that the CSF pool is segregated from that in blood.
Brain Behavior and Immunity 12/2006; 20(6):585-9. · 4.72 Impact Factor
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ABSTRACT: Interleukin-6 increases in skeletal muscle during exercise, and evidence points to Ca2+ as an initiator of IL-6 production. However, the signalling pathway whereby this occurs is unknown. One candidate for Ca2+ -mediated IL-6 induction is calcineurin, an activator of NF-AT. Here we investigated whether skeletal myocytes produce IL-6 in a Ca2+/calcineurin-dependent manner, and whether TNF-alpha, an inducer of IL-6, is affected by these stimuli. Human skeletal muscle cell cultures were stimulated with ionomycin time-and dose-dependently to elevate intracellular Ca2+ levels, with or without addition of cyclosporin A (CSA); a calcineurin inhibitor. mRNA was extracted from myocytes and analysed for IL-6 and TNF-alpha gene expression. IL-6 mRNA increased time- and dose-dependently with ionomycin stimulation, an effect that was blunted by approximately 75% in the presence of CSA. In contrast, TNF-alpha gene expression was decreased by approximately 70% in response to ionomycin treatment, but increased in response to addition of CSA. These data demonstrate that IL-6 and TNF-alpha are regulated differentially in skeletal muscle cells in response to a Ca2+ stimulus. Blocking the calcineurin pathway resulted in inhibition of the IL-6 response to ionomycin, whereas TNF-alpha increased by addition of CSA, further indicating a differential regulation of IL-6 and TNF-alpha in human skeletal myocytes.
Cytokine 12/2006; 36(3-4):141-7. · 3.02 Impact Factor
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ABSTRACT: To examine muscle and blood metabolites during soccer match play and relate it to possible changes in sprint performance.
Thirty-one Danish fourth division players took part in three friendly games. Blood samples were collected frequently during the game, and muscle biopsies were taken before and after the game as well as immediately after an intense period in each half. The players performed five 30-m sprints interspersed by 25-s recovery periods before the game and immediately after each half (N=11) or after an intense exercise period in each half (N=20).
Muscle lactate was 15.9+/-1.9 and 16.9+/-2.3 mmol.kg d.w. during the first and second halves, respectively, with blood lactate being 6.0+/-0.4 and 5.0+/-0.4 mM, respectively. Muscle lactate was not correlated with blood lactate (r=0.06-0.25, P>0.05). Muscle glycogen decreased (P<0.05) from 449+/-23 to 255+/-22 mmol.kg d.w. during the game, with 47+/-7% of the muscle fibers being completely or almost empty of glycogen after the game. Blood glucose remained elevated during the game, whereas plasma FFA increased (P<0.05) from 0.45+/-0.05 to 1.37+/-0.23 mM. Mean sprint time was unaltered after the first half, but longer (P<0.05) after the game (2.8+/-0.7%) as well as after intense periods in the first (1.6+/-0.6%) and second halves (3.6+/-0.5%). The decline in sprint performance during the game was not correlated with muscle lactate, muscle pH, or total glycogen content.
Sprint performance is reduced both temporarily during a game and at the end of a soccer game. The latter finding may be explained by low glycogen levels in individual muscle fibers. Blood lactate is a poor indicator of muscle lactate during soccer match play.
Medicine & Science in Sports & Exercise 06/2006; 38(6):1165-74. · 4.43 Impact Factor
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ABSTRACT: The cytokine interleukin-6 (IL-6) exerts it actions via the IL-6 receptor (IL-6R) in conjunction with the ubiquitously expressed gp130 receptor. IL-6 is tightly regulated in response to exercise, being affected by factors such as exercise intensity and duration, as well as energy availability. Although the IL-6 response to exercise has been extensively studied, little is known about the regulation of the IL-6R response. In the present study, we aimed to investigate the effect of exercise, training, and glycogen availability, factors known to affect IL-6, on the regulation of gene expression of the IL-6R in human skeletal muscle. Human subjects performed either 10 wk of training with an acute exercise bout before and after the training period, or a low-glycogen vs. normal-glycogen acute exercise trial. The IL-6R mRNA response was evaluated in both trials. In response to acute exercise, an increase in IL-6R mRNA levels was observed. Neither training nor intramuscular glycogen levels had an effect on the IL-6R mRNA response to exercise. However, after 10 wk of training, the skeletal muscle expressed a higher mRNA level of IL-6R compared with before training. The present study demonstrated that the IL-6R gene expression levels in skeletal muscle are increased in response to acute exercise, a response that is very well conserved, being affected by neither training status nor intramuscular glycogen levels, as opposed to IL-6. However, after the training period, IL-6R mRNA production was increased in skeletal muscle, suggesting a sensitization of skeletal muscle to IL-6 at rest.
Journal of Applied Physiology 01/2006; 99(6):2075-9. · 3.75 Impact Factor
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ABSTRACT: Contracting muscle fibers produce and release IL-6, and plasma levels of this cytokine are markedly elevated in response to physical exercise. We recently showed autocrine regulation of IL-6 in human skeletal muscle in vivo and hypothesized that this may involve up-regulation of the IL-6 receptor. Therefore, we investigated IL-6 receptor regulation in response to exercise and IL-6 infusion in humans. Furthermore, using IL-6-deficient mice, we investigated the role of IL-6 in the IL-6 receptor response to exercise. Human skeletal muscle biopsies were obtained in relation to: 3 h of bicycle exercise and rest (n=6+5), or recombinant human IL-6 infusion (rhIL-6) or saline infusion (n=6+6). We further obtained skeletal muscle samples from IL-6 knockout (KO) mice and wild-type C57/BL-6 mice in response to a 1-h bout of exercise. In exercising human skeletal muscle, IL-6 receptor mRNA increased sixfold with a peak at 6 h postexercise. Detection of the IL-6 receptor protein by immunohistochemistry revealed a pronounced staining following exercise that was primarily located at the cell membrane of the muscle fibers, whereas muscle gp130 expression and plasma levels of soluble IL-6 receptor were unaffected. Infusion of rhIL-6 to humans had no effect on the mRNA level of the IL-6 receptor, whereas there was an increase at the protein level. IL-6 receptor mRNA increased similarly in muscle of both IL-6 KO mice and wild-type mice in response to exercise. In conclusion, exercise increases IL-6 receptor production in human skeletal muscle. This effect is most prominent 6 h after the end of the exercise bout, suggesting a postexercise-sensitizing mechanism to IL-6 when plasma IL-6 is concomitantly low. Exercise-induced increases in IL-6 receptor mRNA most likely occurs via an IL-6 independent mechanism as shown in IL-6 KO mice and the human rhIL-6 infusion study, whereas IL-6 receptor protein levels are responsive to elevated plasma IL-6 levels.
The FASEB Journal 08/2005; 19(9):1181-3. · 5.71 Impact Factor
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ABSTRACT: Leptin, an adipose tissue-derived cytokine, is correlated with adipose mass as obese persons have increased levels of leptin that decrease with weight loss. Previous studies demonstrate that high-energy-expenditure exercise decreases circulating leptin levels, whereas low-energy-expenditure exercise has no effect. We aimed to test the hypothesis that acute exercise reduced leptin mRNA levels in human adipose tissue and that this effect would be ameliorated by carbohydrate supplementation. Because exercise markedly increases circulating IL-6 and epinephrine, we investigated whether the changes in leptin seen with acute exercise could be mediated by IL-6 or epinephrine infusion. Abdominal subcutaneous adipose tissue mRNA and plasma levels of leptin were measured in healthy men in response to 3-h ergometer exercise with or without carbohydrate (CHO) ingestion (n = 8) and in response to infusion with recombinant human (rh)IL-6 (n = 11) or epinephrine (n = 8) or saline. Plasma leptin declined in response to exercise (P < 0.05) compared with rest, whereas mRNA expression in adipose tissue was unaffected. The exercise-induced decrease in plasma leptin was attenuated by CHO ingestion (P < 0.001). A 3-h epinephrine infusion decreased plasma leptin (P < 0.001) to the same level seen with 3 h of exercise, whereas leptin levels were unaffected by rhIL-6 infusion. In conclusion, both acute exercise and epinephrine infusion decreased plasma leptin to a similar extent, whereas there was no effect with rhIL-6 infusion. Acute exercise solely affected leptin plasma levels, as mRNA levels were unchanged. The exercise-induced decrease in circulating leptin was counteracted by CHO ingestion, suggesting a posttranscriptional regulatory mechanism of leptin involving substrate availability.
Journal of Applied Physiology 06/2005; 98(5):1805-12. · 3.75 Impact Factor
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ABSTRACT: Skeletal muscle has been recognized as an endocrine organ, and muscle cell cultures express several cytokines with potential hormonal effects. Interleukin-8 (IL-8), a chemokine, which induces angiogenesis, is expressed in working muscles; however, the cell source of origin has not been identified. We aimed to elucidate if IL-8 protein is: (1) expressed in contracting muscle fibres and (2) whether there is a release of IL-8 from exercising muscle. Seventeen healthy male volunteers were included in two independent protocols: 3 h of ergometer bicycle exercise at 60% of VO2,max (n = 6) or rest (n = 5), and 3 h of two-legged knee-extensor exercise at 60% of maximal workload (n = 6). Repetitive muscle biopsy samples were obtained from the vastus lateralis in all experiments. A marked increase in IL-8 mRNA was found in muscle biopsy samples obtained after exercise. A marked IL-8 protein expression was demonstrated within the cytoplasm of muscle fibres in biopsy samples obtained in the recovery phase following 3 h of bicycle exercise, and the peak occurred 3-6 h postexercise. A small transient net release of IL-8 from working muscle was found at 1.5 h of knee-extensor exercise. However, the small release of IL-8 from muscle did not result in an increase in the systemic plasma concentration of IL-8, suggesting that muscle-derived IL-8 may play a local role, e.g. in angiogenesis.
The Journal of Physiology 04/2005; 563(Pt 2):507-16. · 4.72 Impact Factor
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ABSTRACT: We evaluated whether peripheral ammonia production during prolonged exercise enhances the uptake and subsequent accumulation of ammonia within the brain. Two studies determined the cerebral uptake of ammonia (arterial and jugular venous blood sampling combined with Kety-Schmidt-determined cerebral blood flow; n = 5) and the ammonia concentration in the cerebrospinal fluid (CSF; n = 8) at rest and immediately following prolonged exercise either with or without glucose supplementation. There was a net balance of ammonia across the brain at rest and at 30 min of exercise, whereas 3 h of exercise elicited an uptake of 3.7 +/- 1.3 micromol min(-1) (mean +/-s.e.m.) in the placebo trial and 2.5 +/- 1.0 micromol min(-1) in the glucose trial (P < 0.05 compared to rest, not different across trials). At rest, CSF ammonia was below the detection limit of 2 microm in all subjects, but it increased to 5.3 +/- 1.1 microm following exercise with glucose, and further to 16.1 +/- 3.3 microm after the placebo trial (P < 0.05). Correlations were established between both the cerebral uptake (r2 = 0.87; P < 0.05) and the CSF concentration (r2 = 0.72; P < 0.05) and the arterial ammonia level and, in addition, a weaker correlation (r2 = 0.37; P < 0.05) was established between perceived exertion and CSF ammonia at the end of exercise. The results let us suggest that during prolonged exercise the cerebral uptake and accumulation of ammonia may provoke fatigue, e.g. by affecting neurotransmitter metabolism.
The Journal of Physiology 03/2005; 563(Pt 1):285-90. · 4.72 Impact Factor
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ABSTRACT: Skeletal muscle has been recognized as an endocrine organ, and muscle cell cultures express several cytokines with potential hormonal effects. Interleukin-8 (IL-8), a chemokine, which induces angiogenesis, is expressed in working muscles; however, the cell source of origin has not been identified. We aimed to elucidate if IL-8 protein is: (1) expressed in contracting muscle fibres and (2) whether there is a release of IL-8 from exercising muscle. Seventeen healthy male volunteers were included in two independent protocols: 3 h of ergometer bicycle exercise at 60% of (n= 6) or rest (n= 5), and 3 h of two-legged knee-extensor exercise at 60% of maximal workload (n= 6). Repetitive muscle biopsy samples were obtained from the vastus lateralis in all experiments. A marked increase in IL-8 mRNA was found in muscle biopsy samples obtained after exercise. A marked IL-8 protein expression was demonstrated within the cytoplasm of muscle fibres in biopsy samples obtained in the recovery phase following 3 h of bicycle exercise, and the peak occurred 3–6 h postexercise. A small transient net release of IL-8 from working muscle was found at 1.5 h of knee-extensor exercise. However, the small release of IL-8 from muscle did not result in an increase in the systemic plasma concentration of IL-8, suggesting that muscle-derived IL-8 may play a local role, e.g. in angiogenesis.
The Journal of Physiology 02/2005; 563(2):507 - 516. · 4.72 Impact Factor
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ABSTRACT: Contracting skeletal muscles produce and release the cytokine interleukin (IL)-6 and this release is augmented by the presence of low muscle glycogen. Since muscle metabolism in elderly subjects relies on glycogen more than younger subjects, it is possible that aging is associated with an altered production of muscle-derived IL-6 during exercise. To test the relation between aging and muscle-derived IL-6, seven healthy elderly males, mean age 70+/-1 (SEM) yr and six healthy young males, mean age 26+/-2 (SEM) yr performed three hours of dynamic knee-extensor exercise at 50% of maximal work load (Wmax). IL-6 mRNA and glycogen in muscles were analysed and the IL-6 release were estimated before, during and after the exercise. Although the absolute work load in the elderly was less than half of that in the young, 41.1+/-3.1 W and 92.5+/-4.0 W, respectively, the muscle glycogen utilization after three hours of exercise did not differ between groups, 238.7+/-52.4 and 245.2+/-74.0 mmol/kg muscle in elderly and young, respectively. This could explain that the IL-6 release and the IL-6 mRNA amplification increased during exercise with no difference between groups, two-way ANOVA-P = 0.50 and 0.45, respectively. In conclusion, elderly healthy people maintain the capacity to produce and release IL-6 in response to dynamic exercise, with no difference compared to young individuals furthermore, glycogen utilization expressed in changes of glycogen related to muscle mass was equal in elderly and young subject at 50 % of Wmax.
Exercise immunology review 02/2004; 10:42-55. · 2.79 Impact Factor
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ABSTRACT: Prolonged exercise is associated with increased plasma levels of the cytokine interleukin-6 (IL-6). Both circulating catecholamine levels and exercise intensity have been related to the exercise-derived IL-6. During hypoxia and acclimatization, changes in sympathetic activity is seen, and also a given workload becomes more intense in hypoxia. Therefore, hypoxia offers a unique opportunity to study the effect of catecholamines and intensity on exercise-derived IL-6. In the present study, eight Danish sea-level residents performed 60 min of cycle ergometer exercise at sea level (SL) (154 W, 45% maximal O(2) consumption, VO(2)max), in acute (AH) and chronic hypoxia (CH), at the same absolute ((abs)) (AH(abs)=154 W, 54% VO(2)max; CH(abs)=154 W, 59% VO(2)max) and same relative ((rel)) (AH(rel)=130 W, 46% VO(2)max; CH(rel)=120 W, 44% VO(2)max) workload. We hypothesized that the IL-6 response to exercise at the same absolute workload would be augmented during hypoxia compared with sea level, and that these changes would not correlate with changes in catecholamines. In AH(abs) (2.35 pg.ml(-1)) and CH(abs) (3.34 pg.ml(-1)) the IL-6 response to exercise was augmented ( p<0.05) compared with that at sea level (0.78.ml(-1)). In addition, after 60 min of bicycling at sea level, AH(rel) (1.02 pg.ml(-1)) and CH(rel) (1.31 pg.ml(-1)) resulted in similar IL-6 responses. The augmented IL-6 response during AH(abs) and CH(abs) did not match changes in circulating catecholamine levels when comparing all trials. We conclude that the plasma IL-6 concentration during exercise in hypoxia is intensity dependent, and that factors other than catecholamine levels are more important for its regulation.
Arbeitsphysiologie 01/2004; 91(1):88-93. · 2.15 Impact Factor
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ABSTRACT: Heat shock protein (Hsp) 72 is a cytosolic stress protein that is highly inducible by several factors including exercise. Hsp60 is primarily mitochondrial in cellular location, plays a key role in the intracellular protein translocation and cytoprotection, is increased in skeletal muscle by exercise, and is found in the peripheral circulation of healthy humans. Glucose deprivation increases Hsp72 in cultured cells, whereas reduced glycogen availability elevates Hsp72 in contracting human skeletal muscle. To determine whether maintained blood glucose during exercise attenuates the exercise-induced increase in intramuscular and circulating Hsp72 and Hsp60, 6 males performed 120 minutes of semirecumbent cycling at approximately 65% maximal oxygen uptake on 2 occasions while ingesting either a 6.4% glucose (GLU) or sweet placebo (CON) beverage throughout exercise. Muscle biopsies, obtained before and immediately after exercise, were analyzed for Hsp72 and Hsp60 protein expression. Blood samples were simultaneously obtained from a brachial artery, a femoral vein, and the hepatic vein before and during exercise for the analysis of serum Hsp72 and Hsp60. Leg and hepatosplanchnic blood flow were measured to determine Hsp72-Hsp60 flux across these tissue beds. Neither exercise nor glucose ingestion affected the Hsp72 or Hsp60 protein expression in, or their release from, contracting skeletal muscle. Arterial serum Hsp72 increased (P < 0.05) throughout exercise in both trials but was attenuated (P < 0.05) in GLU. This may have been in part because of the increased (P < 0.05) hepatosplanchnic Hsp72 release in CON, being totally abolished (P < 0.05) in GLU. Serum Hsp60 increased (P < 0.05) after 60 minutes of exercise in CON before returning to resting levels at 120 minutes. In contrast, no exercise-induced increase in serum Hsp60 was observed in GLU. We detected neither hepatosplanchnic nor contracting limb Hsp60 release in either trial. In conclusion, maintaining glucose availability during exercise attenuates the circulating Hsp response in healthy humans.
Cell Stress and Chaperones 01/2004; 9(4):390-6. · 3.01 Impact Factor
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ABSTRACT: Interleukin-6 (IL-6) is a cytokine with immuno-regulatory functions. However, contracting skeletal muscle expresses and subsequently releases IL-6 in high amounts, and recent evidence in IL-6 deficient mice suggests a role of IL-6 in metabolism. Since IL-6 mRNA levels also increase in abdominal adipose tissue in response to exercise, we wanted to examine the possible existence of a positive feedback mechanism between muscle and adipose tissue. We obtained biopsies from human skeletal muscle and abdominal subcutaneous adipose tissue in relation to either 3h of bicycle exercise or recombinant human IL-6 infusion (rhIL-6) or saline infusion. In muscle, IL-6 mRNA increased (p<0.05) immediately after exercise, peaking at this time-point, whereas IL-6 mRNA in adipose tissue increased 1.5-h post exercise (p<0.05) displaying a different kinetic of induction. During rhIL-6 infusion, IL-6 mRNA increased 120-fold in muscle (p<0.05). In conclusion, the present study demonstrates that muscle IL-6 is regulated by an autocrine mechanism at the transcriptional level.
Biochemical and Biophysical Research Communications 10/2003; 310(2):550-4. · 2.48 Impact Factor
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ABSTRACT: The cytokine interleukin (IL)-6 can increase markedly in the circulation during exercise, but whether the liver is a source of this increase is unknown. The aim of this study was to measure IL-6 flux across the hepatosplanchnic tissues in humans. To elevate systemic concentrations of IL-6, six healthy male subjects performed 120 min of semirecumbent cycling, and blood samples were simultaneously obtained from a brachial artery and the hepatic vein before and during exercise for the analysis of IL-6. Hepatosplanchnic blood flow (HBF) was measured using the indocyanine green infusion technique. Net hepatosplanchnic IL-6 balance was calculated from these measures. HBF was 1.3 +/- 0.1 l/min at rest and was not reduced throughout exercise, averaging 1.1 +/- 0.2 l/min. Arterial plasma IL-6 markedly increased (P < 0.05) from 1.8 +/- 0.6 ng/l at rest to 14.3 +/- 3.2 ng/l after 120 min of exercise. The hepatosplanchnic viscera did not contribute to this increase, since there was a net hepatosplanchnic IL-6 uptake (0.8 +/- 0.3 vs. 5.5 +/- 1.9 ng/min, rest vs. 120 min; P < 0.05). These data demonstrate that the hepatosplanchnic viscera remove IL-6 from the circulation in humans. This removal may constitute a mechanism limiting the negative chronic metabolic action of chronically elevated circulating IL-6.
AJP Endocrinology and Metabolism 09/2003; 285(2):E397-402. · 4.75 Impact Factor
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ABSTRACT: The purpose of the present study was to test the hypothesis that a transient increase in plasma IL-6 induces an anti-inflammatory environment in humans. Therefore, young healthy volunteers received a low dose of recombinant human (rh)IL-6 or saline for 3 h. Plasma IL-6 levels during rhIL-6 infusion were approximately 140 pg/ml, corresponding to the levels obtained during strenuous exercise. The infusion of rhIL-6 did not induce enhanced levels of the proinflammatory cytokine TNF-alpha but enhanced the plasma levels of the two anti-inflammatory cytokines IL-1 receptor agonist (IL-1ra) and IL-10 compared with saline infusion. In addition, C-reactive protein increased 3 h post-rhIL-6 infusion and was further elevated 16 h later compared with saline infusion. rhIL-6 induced increased levels of plasma cortisol and, consequently, an increase in circulating neutrophils and a decrease in the lymphocyte number without effects on plasma epinephrine, body temperature, mean arterial pressure, or heart rate. In conclusion, this study demonstrates that physiological concentrations of IL-6 induce an anti-inflammatory rather than an inflammatory response in humans and that IL-6, independently of TNF-alpha, enhances the levels not only of IL-1ra but also of IL-10. Furthermore, IL-6 induces an increase in cortisol and, consequently, in neutrocytosis and late lymphopenia to the same magnitude and with the same kinetics as during exercise, suggesting that muscle-derived IL-6 has a central role in exercise-induced leukocyte trafficking.
AJP Endocrinology and Metabolism 09/2003; 285(2):E433-7. · 4.75 Impact Factor
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Gerrit van Hall, Adam Steensberg,
Massimo Sacchetti,
Christian Fischer,
Charlotte Keller,
Peter Schjerling,
Natalie Hiscock,
Kirsten Møller,
Bengt Saltin,
Mark A Febbraio,
Bente K Pedersen
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ABSTRACT: Although IL-6 is a key modulator of immune function, it also plays a role in regulating substrate metabolism. To determine whether IL-6 affects lipid metabolism, 18 healthy men were infused for 3 h with saline (Con; n = 6) or a high dose (High-rhIL6; n = 6) or a low dose (Low-rhIL6; n = 6) of recombinant human IL-6 (rhIL-6). The IL-6 concentration during Con, Low-rhIL6, and High-rhIL6 was at a steady state after 30 min of infusion at approximately 4, 140, and 320 pg/ml, respectively. Either dose of rhIL-6 was associated with a similar increase in fatty acid (FA) concentration and endogenous FA rate of appearance (R(a)) from 90 min after the start of the infusion. The FA concentration and FA R(a) continued to increase until the cessation of rhIL-6 infusion, reaching levels approximately 50% greater than Con values. The elevated levels reached at the end of rhIL-6 infusion persisted at least 3 h postinfusion. Triacylglycerol concentrations were unchanged during rhIL-6 infusion, whereas whole body fat oxidation increased after the second hour of rhIL-6 infusion. Of note, during Low-rhIL6, the induced elevation in FA concentration and FA R(a) occurred in the absence of any change in adrenaline, insulin, or glucagon, and no adverse side effects were observed. In conclusion, the data identify IL-6 as a potent modulator of fat metabolism in humans, increasing fat oxidation and FA reesterification without causing hypertriacylglyceridemia.
Journal of Clinical Endocrinology & Metabolism 08/2003; 88(7):3005-10. · 6.50 Impact Factor
