Elsevier

Medical Hypotheses

Volume 62, Issue 5, May 2004, Pages 759-765
Medical Hypotheses

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response

https://doi.org/10.1016/j.mehy.2003.11.030Get rights and content

Abstract

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients. Second, the activation of the protein kinase R enzyme, a characteristic feature in atleast subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasidilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.

Introduction

To date, the most widely used criteria used to establish the medical diagnosis of `Chronic fatigue syndrome (CFS)' are those reported in 1994 by the Center for Disease Control and Prevention [1]. According to this operational definition, a CFS patient presents with severe fatigue and a number of other symptoms (myalgia, arthralgia, low-grade fever, concentration difficulties), of atleast six months duration. The symptoms are not improved by bed rest and may be aggravated by physical or mental activity [1], [2]. Importantly, any active medical condition that may explain the presence of the symptoms prohibits the diagnosis of CFS. Although CFS affects both sexes and all age groups, the typical patient is a middle-class Caucasian women in her thirties. Since the pathogenesis of the illness remains to be elucidated [3], the natural history of adult patients with CFS is poor [4]. Our current understanding of the disease mechanisms of CFS points to both physical and psychological impairments [5].

Previous research has shown that patients with CFS present with an abnormal exercise response and exacerbation of symptoms after physical activity. Some of the main findings were a reduction in maximal oxygen uptake [6], [7], [8], [9], [10], reduction in peak heart rate [9], [10] and peak power output [7], earlier exhaustion [7], [8], [9], [10], and accelerated glycolysis with increased lactate production [11]. Contrary to these findings, Sargent et al. [12], Rowbottom et al. [13], and Kent-Braun et al. [14] found that the aerobic capacity of CFS patients lies within the low normal range. The highly heterogeneous nature of the CFS population and the lack of uniformity in the utilised diagnostic criteria preclude pooling of data and hence to draw firm conclusions. Still, we conclude that at least a subgroup of CFS patients present with an abnormal response to exercise. In addition, since several exercise capacity parameters (e.g. functional aerobic impairment, body-weight adjusted peak oxygen uptake, exercise duration) correlated with activity limitations/participation restrictions [15], evidence supporting the clinical importance of impairments in cardiorespiratory fitness in CFS patients was provided. Importantly, the exacerbation of symptoms after exercise is seen only in the CFS population, and not in fatigue-associated disorders such as depression, rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis [16]. To date, the exact cause of the abnormal exercise response in CFS remains to be revealed. Snell and colleagues [17] showed that CFS patients with evidence of a deregulated 2,5-oligoadenylate (2-5A) synthetase/RNase (ribonuclease) L pathway have a lower peak oxygen uptake than the CFS patients without the intracellular immune deregulation, suggesting a link between immunopathology and exercise capacity in CFS. This manuscript explores the hypothetical associations between exercise pathophysiology and the recent advances in immunopathology in patients with CFS.

Section snippets

CFS-associated channelopathy might cause muscle weakness and hypoglycemia

The deregulation of the 2-5A synthetase/RNase L pathway in subsets of CFS patients has been reported at length in the scientific literature [18], [19], [20], [21], [22], [23]. Both elastases and calpain are capable of initiating high molecular weight RNase L (83 kDa) proteolysis, generating two major fragments with molecular masses of 37 (a truncated low molecular weight RNase L) and 30 kDa, respectively [24]. By measuring and calculating the amount of low molecular weight protein relative to

Testing the hypotheses

In order to test the above outlined hypotheses, future research should exposure a randomly allocated sample of CFS subjects to a standardized exercise protocol (monitoring cardiorespiratory parameters continuously). Prior to the exercise stress testing, a plebotomy is required in order to monitor the 83 kDa RNase L proteolysis, biochemical parameters (potassium, etc.), NO concentration, PKR activity, and NF-κB activity. Furthermore, it would be of interest to monitor possible changes in both

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