Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response
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
References (72)
- et al.
Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome
Am. J. Med.
(1996) - et al.
Skeletal muscle metabolism in the chronic fatigue syndrome: in vivo assessment by 31P nuclear magnetic resonance spectroscopy
Chest
(1992) - et al.
Complement activation in a model of chronic fatigue syndrome
J. Allergy Clin. Immunol.
(2003) - et al.
A 37 kDa 2-5A binding protein as a potential biochemical marker for Chronic Fatigue Syndrome
Am. J. Med.
(2000) - et al.
Cloning and characterization of a RNase L inhibitor
J. Biol. Chem.
(1995) - et al.
Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients
J. Biol. Chem.
(2002) - et al.
Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic fatigue Syndrome
FEMS Immunol. Med. Microbiol.
(1998) - et al.
High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients
FEMS Immunol. Med. Microbiol.
(2002) - et al.
Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome
Neuroscience Letters
(2003) - et al.
Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-γ
Am. J. Pathol.
(2001)
Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome
Neuromusc. Dis.
Mycoplasma fermentans interaction with monocytes/macrophages: molecular basis
Microbes. Infect.
A Mycoplasma fermentans-derived synthetic lipopeptide induces AP-1 and NF-κB activity and cytokine secretion in macrophages via the activation of mitogen-activated protein kinase pathways
J. Biol. Chem.
Chlamydia pneumoniae activates nuclear factor κB and activator protein 1 in human vascular smooth muscle and induces cellular proliferation
J. Surg. Res.
Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation
Cell
Chronic enterovirus infection in patients with postviral fatigue syndrome
Lancet
The Chronic Fatigue Syndrome, a comprehensive approach to its definition and study
Ann. Intern. Med.
Chronic Fatigue Syndrome: a working case definition
Ann. Intern. Med.
Chronic Fatigue Syndrome: new insights and old ignorances
J. Intern. Med.
Use of exercise for treatment of chronic fatigue syndrome
Sports Med.
Psychological adjustment of adolescent girls with chronic fatigue syndrome
Pediatrics
Exercise capacity in chronic fatigue syndrome
Arch. Intern. Med.
Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology
J. Psychosom. Res.
Aerobic work capacity in patients with chronic fatigue syndrome
Brit. Med. J.
Strength and physiological response to exercise in patients with chronic fatigue syndrome
J. Neurol. Neurosurg. Neuropsych.
Maximal oxygen uptake and lactate metabolism are normal in chronic fatigue syndrome
Med. Sci. Sports Exerc.
The physiological response to exercise in chronic fatigue syndrome
J. Chronic Fatigue Syndr.
Central basis of muscle fatigue in chronic fatigue syndrome
Neurology
Disability evaluation in chronic fatigue syndrome: associations between exercise capacity and activity limitations/participation restrictions
Clin. Rehabil.
Physical performance and prediction of 2-5A Synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome
In Vivo
Upregulation of the 2-5A synthetase/Rnase L antiviral pathway associated with chronic fatigue syndrome
Clin. Infect Dis.
Biochemical dysregulation of the 2-5A synthetase/Rnase L antiviral defense pathway in chronic fatigue syndrome
J. Chronic Fatigue Syndr.
Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome
J. Interferon Cytokine Res.
RNase L inhibitor is induced during human immunodeficiency virus type 1 infection and down regulates the 2-5A/Rnase L pathway in human T Cells
J. Virol.
Diversity of ankyrins in the brain
Biochem. Soc. Trans.
Interactions between RNase L ankyrin-like domain and ABC transporters as a possible origin for pain, ion transport, CNS and immune disorders of Chronic Fatigue Immune Dysfunction Syndrome
J. Chronic Fatigue Syndr.
Cited by (21)
Expression of mRNA and protein-protein interaction of the antiviral endoribonuclease RNase L in mouse spleen
2014, International Journal of Biological MacromoleculesCitation Excerpt :Here, we can correlate that the ECM proteins like fibronectin interacts with RNase L and this complex may act as sensors of stress response from the external environment, which upon receiving the stress signals, transmit it to the cells and lead to loss of certain mRNAs and rearrangement of cytoskeletal proteins leading to change in the cell shape. The interaction of RNase L with the ECM, cytoskeletal and contractile proteins of the muscles may be hypothesized to correlate its importance in the etiology of chronic fatigue syndrome (CFS), a disorder characterized with debilitating fatigue in patients with a deregulation of the 2-5A/RNase L pathway involving the presence of a catalytically active truncated form of RNase L (∼37 kDa) and related to extreme muscle fatigue, membrane channelopathy, initiating intracellular hypomagnesaemia in skeletal muscles and also transient hypoglycemia [41,42]. Here, it may be noted that RNase L has been reported to play a role in the regulation of half life of mRNAs during muscle cell differentiation [43].
Chronic fatigue syndrome
2006, LancetCitation Excerpt :Nevertheless, at the tissue level, cytokines such as interleukin 6 might have an important role in CFS, because they are also involved in the stress response and are crucial inducers of sickness behaviour,83–86 which is characterised by avoidance behaviour, apathy, sleepiness, impaired memory and concentration, anorexia, mild fever, and increased sensitivity for pain. The role of RNAse L molecule in the type 1 interferon pathway is unclear.87–89 No specific pattern of cerebral abnormalities in patients with CFS has been found.90
Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study
2019, Oxidative Medicine and Cellular Longevity