Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise
Authors
Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S
Institution
Laboratoire de Physiopathologie Respiratoire (UPRES EA 2201), Faculte de Medecine, Institut Federatif de Recherche Jean Roche, Marseille, France
Background
Because the muscle response to incremental exercise is not well documented in patients suffering from chronic fatigue syndrome (CFS), we combined electrophysiological (compound-evoked muscle action potential, M wave), and biochemical (lactic acid production, oxidative stress) measurements to assess any muscle dysfunction in response to a routine cycling exercise.
Design
This case-control study compared 15 CFS patients to a gender-, age- and weight-matched control group (n=11) of healthy subjects.
Interventions
All subjects performed an incremental cycling exercise continued until exhaustion.
Main outcome measures
We measured the oxygen uptake (VO2), heart rate (HR), systemic blood pressure, percutaneous O2 saturation (SpO2), M-wave recording from vastus lateralis, and venous blood sampling allowing measurements of pH (pHv), PO2 (PvO2), lactic acid (LA), and three markers of the oxidative stress (thiobarbituric acid-reactive substances, TBARS, reduced glutathione, GSH, and ascorbic acid, RAA).
Results
Compared with control, in CFS patients (i) the slope of VO2 versus work load relationship did not differ from control subjects and there was a tendency for an accentuated PvO2 fall at the same exercise intensity, indicating an increased oxygen uptake by the exercising muscles; (ii) the HR and blood pressure responses to exercise did not vary; (iii) the anaerobic pathways were not accentuated; (iv) the exercise-induced oxidative stress was enhanced with early changes in TBARS and RAA and enhanced maximal RAA consumption; and (v) the M-wave duration markedly increased during the recovery period.
Conclusions
The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and postexertional malaise reported by our patients.
Publication
J Intern Med 2005; 257(3): 299–310
Comment by ME Research UK
This intriguing paper by Jammes and colleagues strengthens the arguments for abnormal redox signalling in the muscle of CFS patients. In essence, it reports that exercise — quite intensive bicycling — gives rise to abnormally increased oxidative stress (free radical generation) in ME/CFS patients, and it also reports on an unusual post-exercise increase in the excitability of the vastus lateralis muscle (outer border of the thigh).
As regards the muscle findings, the authors measured compound-evoked muscle action potentials (M-waves) before and after exercise. Recording the M-wave with surface electrodes is a non-invasive means of exploring peripheral muscle fatigue in response to exercise: the M-wave has an initial negative (upwards) deflection, and it is the result of several physiological events, including orthodromic propagation of action potentials down the nerve, acetylcholine release at the neuromuscular junction, and myofibre depolarisation. In the context of this paper, it is best thought of as a mass response; i.e., the sum of the individual action potentials in all of the muscle fibres in response to stimulation, and an indicator of muscle force or power.
An impaired excitation of the muscle fibres is suspected when the M-wave declines and becomes broader. In the ME/CFS patients studied, the latency and amplitude of the M-wave were both normal but there was a marked alteration in muscle excitability (lengthened M-wave duration) which began early after the exercise had stopped and culminated at the end of the 30-minute recovery period, these M-wave changes being totally absent in the control subjects. An increase in post-exertional M-wave duration would automatically lead to a decrease in the maximum response frequency to stimulation — i.e., above a certain frequency ME/CFS patients would not be able to respond physiologically, and this could well account for the reduction in muscle power after exercise reported by patients, and shown by Paul et al 1999 (1). The authors ruled out passive potassium ion flow during excitation or the post-recovery period as the source of the problem. Instead, they suggested that the increase in M-wave duration after exercise was consistent with a breakdown of normal trans-membrane ionic pump activity. This is very much in line with the work of Fulle et al (2) who hypothesised that the characteristic post-exertional fatigue of many ME/CFS patients was due to modifications of the fluidity of membranes of the sarcoplasmic reticulum, central to the spread of action potentials towards the interior of the muscle cell and to the process of contraction.
As regards oxidative stress findings, despite no difference in resting levels of antioxidants between ME/CFS and control groups, the exercise-induced oxidative stress occurred sooner in the ME/CFS patients (at the maximal work rate), lasted longer, and there was a significant enhanced maximal post-exercise decrease in one of the markers of oxidative stress plasma-reduced ascorbic acid (RAA). From their previous work, the authors consider these changes in markers of oxidative stress in ME/CFS patients during the exercise bout to be of real significance. And their findings add to the growing number of reports of increased oxidative stress in people with ME/CFS (for discussion, see the article here). Suffice it to say that it is important to discover the source(s) of these molecules, whether from excessive immune activity, chronic infections or from abnormalities within muscle tissue.
The paper does not determine whether excessive free radical generation is the cause of the muscle symptoms in patients or whether the free radicals are simply a consequence of underlying muscle pathology, but it confirms previous studies that point to positive correlations between muscle symptoms and measures of oxidative stress (3,4). Unfortunately, the authors do not show specimen M-wave traces from control and ME/CFS patients at the sampling periods to give the reader a graphic illustration of these potentially important phenomena, and nor have they made measurements for longer than 30 minutes post-exercise, an important omission given the reports of delayed muscle symptoms in this patient group. These omissions can, however, be rectified by new research, replicating and extending this exciting work.
References
- Paul L, Wood L, Behan WHM, Maclaren WM. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. European Journal of Neurology 1999; 6: 63–9.
- Fulle S, Belia S, Vecchiet J, Morabito C, Vecchiet L, Fano G. Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome. Neuromuscular Disorders 2003; 13: 479–84.
- Vecchiet J, Cipollone F, Falasca K et al. Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome. Neuroscience Letters 2003; 335: 151–4.
- Fulle S, Mecocci P, Fano G et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radical Biology and Medicine 2000; 29: 1252–9.
