Plasma interleukin (IL)‐6 concentration is increased with exercise and it has been demonstrated that contracting muscles can produce IL‐ The question addressed in the present study was whether the IL‐6 production by contracting skeletal muscle is of such a magnitude that it can account for the IL‐6 accumulating in the blood. This was studied in six healthy males, who performed one‐legged dynamic knee extensor exercise for 5 h at 25 W, which represented 40% of peak power output (Wmax). Arterial‐femoral venous (a‐fv) differences over the exercising and the resting leg were obtained before and every hour during the exercise. Leg blood flow was measured in parallel by the ultrasound Doppler technique. IL‐6 was measured by enzyme‐linked immunosorbent assay (ELISA). Arterial plasma concentrations for IL‐6 increased 19‐fold compared to rest. The a‐fv difference for IL‐6 over the exercising leg followed the same pattern as did the net IL‐6 release. Over the resting leg, there was no significant a‐fv difference or net IL‐6 release. The work was produced by 2.5 kg of active muscle, which means that during the last 2 h of exercise, the median IL‐6 production was 6.8 ng min−1 (kg active muscle)−1 (range, 3.96‐9.69 ng min−1 kg−1). The net IL‐6 release from the muscle over the last 2 h of exercise was 17‐fold higher than the elevation in arterial IL‐6 concentration and at 5 h of exercise the net release during 1 min was half of the IL‐6 content in the plasma. This indicates a very high turnover of IL‐6 during muscular exercise. We suggest that IL‐6 produced by skeletal contracting muscle contributes to the maintenance of glucose homeostasis during prolonged exercise.

In humans, the plasma interleukin 6 (IL-6) concentration increases dramatically during low-intensity exercise. Measurements across the working limb indicate that skeletal muscle is the source of IL-6 production. To determine whether energy availability influences the regulation of IL-6 expression during prolonged exercise, six male subjects completed two trials consisting of 180 min of two-legged dynamic knee extensor with either normal or low (~60% of control) pre-exercise muscle glycogen levels. Increases in plasma IL-6 during exercise were significantly higher (P<0.05) in the low-glycogen (16-fold) trial verses the control (10-fold) trial. Transcriptional activation of the IL-6 gene in skeletal muscle was also higher in the low-glycogen trial; it increased by about 40-fold after 90 min of exercise and about 60-fold after 180 min of exercise. Muscle IL-6 mRNA followed a similar but delayed pattern, increasing by more than 100-fold in the low-glycogen trial and by about 30-fold in the control trial. These data demonstrate that exercise activates transcription of the IL-6 gene in working skeletal muscle, a response that is dramatically enhanced when glycogen levels are low. These findings also support the hypothesis that IL-6 may be produced by contracting myofibers when glycogen levels become critically low as a means of signaling the liver to increase glucose production.

Prolonged exercise results in a progressive decline in glycogen content and a concomitant increase in the release of the cytokine interleukin‐6 (IL‐6) from contracting muscle. This study tests the hypothesis that the exercise‐induced IL‐6 release from contracting muscle is linked to the intramuscular glycogen availability. Seven men performed 5 h of a two‐legged knee‐extensor exercise, with one leg with normal, and one leg with reduced, muscle glycogen content. Muscle biopsies were obtained before (pre‐ex), immediately after (end‐ex) and 3 h into recovery (3 h rec) from exercise in both legs. In addition, catheters were placed in one femoral artery and both femoral veins and blood was sampled from these catheters prior to exercise and at 1 h intervals during exercise and into recovery. Pre‐exercise glycogen content was lower in the glycogen‐depleted leg compared with the control leg. Intramuscular IL‐6 mRNA levels increased with exercise in both legs, but this increase was augmented in the leg having the lowest glycogen content at end‐ex. The arterial plasma concentration of IL‐6 increased from 0.6 ± 0.1 ng l−1 pre‐ex to 21.7 ± 5.6 ng l−1 end‐ex. The depleted leg had already released IL‐6 after 1 h (4.38 ± 2.80 ng min−1 (P < 0.05)), whereas no significant release was observed in the control leg (0.36 ± 0.14 ng min−1). A significant net IL‐6 release was not observed until 2 h in the control leg. This study demonstrates that glycogen availability is associated with alterations in the rate of IL‐6 production and release in contracting skeletal muscle.

The aim of the present study was to examine whether IL-6 and TNF-α are expressed in, and released from, human skeletal muscle during exercise. We hypothesized that the skeletal muscle will release IL-6, but not TNF-α, during exercise because of previous observations that TNF-α negatively affects glucose uptake in skeletal muscle. Six healthy, male subjects performed 180 min of two-legged knee-extensor exercise. Muscle samples were obtained from the vastus lateralis of one limb. In addition, blood samples were obtained from a femoral artery and vein. Plasma was analyzed for IL-6 and TNF-α. We detected both IL-6 and TNF-α mRNA in resting muscle samples, and whereas IL-6 increased ( P < 0.05) ∼100-fold throughout exercise, no significant increase in TNF-α mRNA was observed. Arterial plasma TNF-α did not increase during exercise. Furthermore, there was no net release of TNF-α either before or during exercise. In contrast, IL-6 increased throughout exercise in arterial plasma, and a net IL-6 release from the contracting limb was observed after 120 min of exercise ( P < 0.05).

During maximal exercise in humans, fatigue is preceded by reductions in systemic and skeletal muscle blood flow, O 2 delivery and uptake. Here, we examined whether the uptake of O 2 and substrates by the human brain is compromised and whether the fall in stroke volume of the heart underlying the decline in systemic O 2 delivery is related to declining venous return. We measured brain and central haemodynamics and oxygenation in healthy males (n = 13 in 2 studies) performing intense cycling exercise (360 ± 10 W; mean ± s.e.m.) to exhaustion starting with either high (H) or normal (control, C) body temperature. Time to exhaustion was shorter in H than in C (5.8 ± 0.2 versus 7.5 ± 0.4 min, P < 0.05), despite heart rate reaching similar maximal values. During the first 90 s of both trials, frontal cortex tissue oxygenation and the arterial-internal jugular venous differences (a-v diff) for O 2 and glucose did not change, whereas middle cerebral artery mean flow velocity (MCA V mean ) and cardiac output increased by ∼22 and ∼115%, respectively. Thereafter, brain extraction of O 2 , glucose and lactate increased by ∼45, ∼55 and ∼95%, respectively, while frontal cortex tissue oxygenation, MCA V mean and cardiac output declined ∼40, ∼15 and ∼10%, respectively. At exhaustion in both trials, systemicV O 2 declined in parallel with a similar fall in stroke volume and central venous pressure; yet the brain uptake of O 2 , glucose and lactate increased. In conclusion, the reduction in stroke volume, which underlies the fall in systemic O 2 delivery and uptake before exhaustion, is partly related to reductions in venous return to the heart. Furthermore, fatigue during maximal exercise, with or without heat stress, in healthy humans is associated with an enhanced rather than impaired brain uptake of O 2 and substrates.