Plasma interleukin (IL)-6 is highly increased in response to strenuous exercise and the production has been shown to originate from the contracting muscles (Pedersen et al. 2001). However, the exercise-related stimuli and the purpose of this production are at present unknown. The loss of glycogen may play a role in the production (Steensberg et al. 2001). The role of muscle-derived IL-6 could be systemic, but another possibility is that the muscle-derived IL-6 has a local function within the muscles. To look into this possibility, we have investigated whether the expression of IL-6-dependent target genes in the muscle is induced by exercise.
This study investigated the expression of two direct target genes C/EBPβ and C/EBPδ, encoding transcription factors, in the IL-6 signal transduction pathway after exercise. The hypothesis is that the mRNA level for C/EBPβ and C/EBPδ would increase as a result of activation of the IL-6 signal transduction pathway within the muscle.
Muscle biopsies from vastus lateralis were obtained from eight males before, during (1.5 h) and in the hours after running (0, 0.5, 1, 2 and 4 h) at 75 % of VO2,max on a treadmill for 2.5 h. Two control subjects that did not perform exercise were also included. The experimental protocol was approved by the ethics committee and all subjects were informed of the risks and purposes of the study before their written consent was obtained. mRNA for IL-6, C/EBPβ and C/EBPδ were quantified by Northern blotting.
In the exercised muscles C/EBPβ mRNA increased 2-fold at the first time point and remained at that level. C/EBPδ mRNA increased to a 10- to 15-fold elevated level and stayed there until the last time point at 4 h where it dropped to about 2-fold. However, the C/EBPβ mRNA increased in a similar manner in the control subject, whereas only during exercise C/EBPδ mRNA increased to a similar level. At 0-2 h after exercise the increase in C/EBPδ mRNA level was clearly less in the controls. When we looked at the IL-6 mRNA a large increase (more than 10-fold) was seen in the biopsies taken during exercise. A similar increase was seen in one of the controls whereas the other displayed no increase. 0-2 h after exercise the IL-6 mRNA level was 2- to 4-fold increased and returned to basal level at 4 h. The controls remained below a 2-fold increase at these time points.
The data suggest that the sampling procedure itself is influencing the result. The same hole was used twice for taking biopsies and the largest increases in control subjects were seen in the second biopsies. It appears that the invasive action of the biopsy caused production of IL-6 in the local area. However, whereas the increase in C/EBPβ could be explained by the biopsies, the C/EBPδ demonstrated a clear additional exercise effect in the hours after exercise.
In conclusion, the data indicate that the IL-6 signal can be propagated in skeletal muscle, suggesting that the exercise-related IL-6 production represents a local signal within the muscle.
This study was supported by the Danish National Research Foundation (504-14).