Interleukin‐6 production in contracting human skeletal muscle is influenced by pre‐exercise muscle glycogen content

Abstract

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.

Systemic cytokine response following exercise-induced muscle damage in humans

“…However, the kinetics of IL-6 production have shown a progressive increase following muscle-damaging eccentric exercise (10,16). This is in contrast to the rapid decline of IL-6 concentrations following non-damaging concentric exercise of long duration (24,26,27). In agreement with previous findings (16), we found a prolonged increase in IL-6 which could reflect a key role of IL-6 in the repair mechanism after muscle damage (10,24).…”

Myokines in insulin resistance and type 2 diabetes

“…Most data are available for IL-6, which has been intensively studied during the past decades. Upon muscle contraction, IL-6 is released into the circulation the amount of which is dependent on intensity and duration of exercise [10] and the energy status of a muscle, as determined by pre-exercise glycogen content [11]. This leads to an acute increase of IL-6 plasma levels during exercise, the main sources of which are the myofibres [12].…”

“…These pathways mediate increased glucose uptake, GLUT4 translocation and glycogen synthesis on acute exposure to IL-6 (Table 1) [18][19][20]. Interestingly, ingestion of glucose during exercise blunts IL-6 secretion from contracting muscle [21], and a low pre-exercise muscular glycogen level augments the induction of IL-6 expression and release by exercise [11,22]. Exercise-induced adaptation in skeletal muscle also includes an increase in pre-exercise muscular glycogen content.…”

Hepatosplanchnic clearance of interleukin-6 in humans during exercise

“…During exercise, neither the immune cells (34) nor the adipose tissue (19) contributes to the increase in plasma IL-6, and contribution from the brain (24) and the peritendon (16) is small. Rather, muscle contraction rapidly increases intramuscular IL-6 gene expression (7,15,23,33,35,37) and the nuclear transcriptional activity of IL-6 (15). Importantly, IL-6 protein is released from skeletal muscle during prolonged exercise (7,8,32,33,35), and cultured human primary muscle cells are capable of increasing IL-6 mRNA when incubated with the calcium ionophore ionomycin (14).…”

“…Rather, muscle contraction rapidly increases intramuscular IL-6 gene expression (7,15,23,33,35,37) and the nuclear transcriptional activity of IL-6 (15). Importantly, IL-6 protein is released from skeletal muscle during prolonged exercise (7,8,32,33,35), and cultured human primary muscle cells are capable of increasing IL-6 mRNA when incubated with the calcium ionophore ionomycin (14). Therefore, it is likely that myocytes produce IL-6 in response to physical stress, and production of IL-6 by such tissue can account for most of the exercise-induced increase in plasma levels of this cytokine.…”