Robinson M, Gray SR, Watson MS, Kennedy G, Hill A, Belch JJF, Nimmo MA
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
The aim of the current study was to investigate the levels of interleukin-6 (IL-6), its soluble receptors (sIL-6R and sgp130) and F(2)-isoprostanes, at rest and during exercise, in patients with chronic fatigue syndrome (CFS).
Six male CFS patients and six healthy controls performed an incremental exercise test to exhaustion and a submaximal exercise bout to exhaustion. Blood samples taken in the submaximal test at rest, immediately post-exercise and 24 h post-exercise were analyzed for IL-6, sIL-6R, sgp130 and F(2)-isoprostanes. A further 33 CFS and 33 healthy control participants gave a resting blood sample for IL-6 and sIL-6R measurement.
During the incremental exercise test only power output at the lactate threshold was lower (P<0.05) in the CFS group. F(2)-isoprostanes were higher (P<0.05) in CFS patients at rest and this difference persisted immediately and 24 h post-exercise. The exercise study found no differences in IL-6, sIL-6R or sgp130 at any time point between groups. In the larger resting group, there were no differences in IL-6 and sIL-6R between CFS and control groups.
This investigation has demonstrated that patients with CFS do not have altered plasma levels of IL-6, sIL-6R or sgp130 either at rest or following exercise. F(2)-isoprostanes, however, were consistently higher in CFS patients.
Comment by ME Research UK
Muslce pain, fatigue and malaise after exercise – sometimes developing 24 to 48 hours later – are considered to be characteristic of ME/CFS. There have been some suggestions that the “fatigue” in the illness could be associated with limitations in the use or supply of fuel by the tissues. If so, an understanding of interleukin-6 (IL-6) and its associated receptors could be important, since IL-6 is produced by working skeletal muscle and is also a key component of the body’s response to the illness.
Some studies have indicated that ME/CFS patients do not have raised levels of IL-6 and other cytokines in the blood at rest. However, IL-6 requires receptors to be biologically active, so it is important that both IL-6 and its receptors are investigated. As it is exercise that brings on symptoms in most people with ME/CFS – at least in the early stages of the illness – perhaps researchers ought to be looking at changes during exercise rather than at rest?
It was this aspect that particularly interested Professor Myra Nimmo who is a metabolic physiologist internationally renowned for work in exercise physiology. She says, “
Exercise offers the opportunity to examine patients in an exacerbated state, yet many studies to date have not clearly categorised the exercise regimen and, since incremental maximal tests are essentially limited by cardiorespiratory fitness, metabolic limitations may be more clearly identified through the use of a sub-maximal exercise protocol.”
To explore whether IL-6 and its receptors might be involved in the reduction in exercise performance and poor recovery from exercise seen in these patients, Prof. Nimmo and Mark Robinson conducted an ME Research UK-funded pilot study of six men with ME/CFS and six healthy control subjects matched for age, physical activity and body mass.
Each participant undertook an exercise bout at 90% lactate threshold, allowing a “matching” of the metabolic load between controls and patients – a refinement missing from previous studies. All volunteers were required to visit the laboratory twice, the first visit for identification of the lactate threshold. On the second occasion, subjects were exercised at their identified exercise load in the morning before eating. Subjects were then given standardised meals for the following 24 hours (not very palatable, we’re told!) and blood samples were taken before and after exercise, and at regular intervals throughout this period. A further 33 CFS and 33 healthy control participants gave a resting blood sample for measurement of IL-6 and soluble IL-6R levels.
During the incremental exercise test, the physiological responses of both groups were closely similar, except that the power output at the lactate threshold was 28% lower in the ME/CFS group than in the matched controls (p<0.05). In addition, F2-isoprostanes – which indicate oxidative stress – were higher in patients than in controls at rest (p<0.05), as well as after exercise and after 24 hours.
However, the study found no differences in IL-6 or its receptors between patients and controls at any time point, and in the larger study there were no differences in resting IL-6 levels or its receptors.
What are we to make of these findings? Well, the lack of a difference in either IL-6 or its soluble receptor at rest or during exercise suggests that “transignaling” is unlikely to be involved in the pathology of ME/CFS. This is a negative result yet an important one.
However, the results do confirm previous ME Research UK-funded work (by Dr Kennedy in Dundee) showing raised levels of F2-isoprostanes in ME/ CFS patients at rest, and Prof. Nimmo has now shown that these levels remain high during exercise and in the recovery period. Indeed, the level of isoprostanes in the “rested” ME/CFS patients was as great on average than that reached by the healthy controls after exercise!
As isoprostanes also act as vasoconstrictors, their presence, accompanied by additional free radicals during exercise, may be responsible for some of the clinical symptoms seen in ME/CFS, such as joint pain and post-exercise illness.
This essay is an extract from our article (pdf 519 KB) in the Autumn 2009 issue of Breakthrough.