From Pain, April 2015.
Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome
Staud, Roland; Mokthech, Meriem; Price, Donald D.; Robinson, Michael E.
Departments of (a) Medicine, (b)Oral and Maxillofacial Surgery, and (c)Clinical and Health Psychology, University of Florida, Gainesville, FL, USA.
Abstract
Patients with chronic fatigue syndrome (CFS) frequently demonstrate intolerance to physical exertion that is often reported as increased and long-lasting fatigue. Because no specific metabolic alterations have been identified in CFS patients, we hypothesized that sensitized fatigue pathways become activated during exercise corresponding with increased fatigue.
After exhausting handgrip exercise, muscle metabolites were trapped in the forearm tissues of 39 CFS patients and 29 normal control (NC) by sudden occlusion for up to 5 minutes. A nonocclusive condition of similar duration was used as control. Repeated fatigue and pain ratings were obtained before and after exercise.
Mechanical and heat hyperalgesia were assessed by quantitative sensory testing. All subjects fulfilled the 1994 Fukuda Criteria for CFS. Normal control and CFS subjects exercised for 6.6 (2.4) and 7.0 (2.7) minutes (P > 0.05). Forearm occlusion lasted for 4.7 (1.3) and 4.9 (1.8) minutes in NC and CFS subjects, respectively (P > 0.05).
Although fatigue ratings of CFS subjects increased from 4.8 (2.0) to 5.6 (2.1) visual analogue scale (VAS) units during forearm occlusion, they decreased from 5.0 (1.8) to 4.8 (2.0) VAS units during the control condition without occlusion (P = 0.04).
A similar time course of fatigue ratings was observed in NC (P > 0.05), although their ratings were significantly lower than those of CFS subjects (P < 0.001). Quantitative sensory testing demonstrated heat and mechanical hyperalgesia in CFS subjects.Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise-related fatigue in CFS patients consistent with sensitization of fatigue pathways. Future interventions that reduce sensitization of fatigue pathways in CFS patients may be of therapeutic benefit.
From PLOS One, open access journal, 2 April 2015.
Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome
Audrey E. Brown(1), David E. Jones(1,2), Mark Walker(1,2), Julia L. Newton(2,3).
1) Institute of Cellular Medicine, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
2) Newcastle Hospitals, NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
Julia L. Newton
3) Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom
Corresponding Author: Email: julia.newton@ncl.ac.uk
Abstract
BACKGROUND
Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS.
To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.
METHODS
Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.
RESULTS
In the basal state, CFS cultures showed increased myogenin expres
sion but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells.
In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect.
IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.
CONCLUSION
EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells.
We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6.
The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.
From CNS & Neurological Disorders – Drug Targets, 25 March 2015. [Epub ahead of print].
The Role of Toll-like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach?
Gambuzza ME, Salmeri FM, Soraci L, Soraci G, Sofo V, Marino S, Bramanti P.
Ministry of Health, Territorial Office of Messina, Italy. gambuzza2002@yahoo.it.
Abstract
Perturbations in immune processes play an important role in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), a multifactorial disorder mainly characterized by severe and prolonged fatigue and typically affecting a variety of bodily systems including the immune system.
Recent reports have shown that CFS/ME is an inflammatory disorder may be associated with autoimmune responses, mainly characterized by reduced functional activity of most immune cells, including neutrophils, natural killer cells, monocytes/macrophage and dendritic cells, together with dysregulations in cytokine levels, responsible for changes in the adaptive immune system.
Interactions between gut microorganisms and host immune function have been shown to contribute to aberrant inflammation in CFS/ME patients.
Commensal and/or pathogen-associated molecular patterns detected by Toll-like receptors (TLRs) expressed on intestinal epithelial cells appear to trigger inflammatory signaling cascade leading to neuroinflammation and neurodegeneration. This paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting.
From Advances in Psychosomatic Medicine, 30 March 1015.
Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues.
Romano GF, Tomassi S, Russell A, Mondelli V, Pariante CM.
Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK.
Abstract
There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS).
Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined.
Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM.
Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes.
However, to what extent these systems' abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified.
From Fatigue: Biomedicine, Health & Behavior, 27 March 2015 (e-published before print).
Brain-derived neurotrophic factor concentration may not be depressed in chronic fatigue syndrome
David M. Patrick(a,b,*), Ruth R. Miller(a,b), Theodore Steiner(c), Jennifer L. Gardy(b), Shoshana M. Parker(d) & Patrick Tang(b,e,f)
a) School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
b) British Columbia Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC, Canada V5Z 4R4
c) Department of Medicine, University of British Columbia, 452D Heather Pavilion East, VGH, 2733 Heather Street, Vancouver, BC, Canada V5Z 3J5
d) Centre for Health Evaluation and Outcome Sciences, 588-1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6
e) Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
f) Laboratory Services, British Columbia Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC, Canada V5Z 4R4
Abstract
Due to its effect on the central nervous system, brain-derived neurotrophic factor (BDNF) has been hypothesized to be involved in a number of neurodegenerative and psychiatric disorders. Recently, BDNF was also reported to be significantly lower in patients with chronic fatigue syndrome (CFS) and multiple sclerosis patients, than in healthy controls.
We tried to repeat this observation in 25 patients with CFS matched to 25 healthy controls and 11 patients with systemic lupus erythematosus. Our study did not find significant differences in BDNF between groups.
Furthermore, we investigated the relationship between BDNF levels and fatigue within CFS sufferers using the fatigue severity score and found no correlation between the two measures.
Our findings act as a caution that results should be replicated in independent laboratories for validation, and we would welcome more research in this area.
From Biophysical Chemistry, 4 April 2015 (e-published before print).
In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome
Nicor Lengert, Barbara Drossel
Institute for Condensed Matter Physics, Technische Universität Darmstadt, Hochschulstr. 6, 64289 Darmstadt, Germany. nicor@fkp.tu-darmstadt.de
Highlights
• Metabolite dynamics in skeletal muscles are simulated during high intensity exercise.
• We take into account exercise induced purine nucleotide loss and de novo synthesis.
• A reduced mitochondrial capacity is assumed for CFS patients.
• CFS simulations exhibit critically low levels of ATP and a prolonged recovery time.
• Additionally an increased acidosis and lactate accumulation is observed in CFS.
Abstract
Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood.
A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients.
To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery.
CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress.
Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.
The last abstract from “Biophysical Chemistry” (& particularly the summary in the last 2 paragraphs) look very significant for further research.
This article shows that exertion intolerance in ME is not a new disease but is the biochemical response to inadequate ATP availability due to mitochondrial dysfunction. It is almost universally believed that the only pathway to provide more ATP is enhanced glycolysis which produces lactate as well as ATP. Evidence for an alternative pathway was found in neutrophils by Booth et al (2012), and this present article shows that this alternative pathway (which is also anaerobic) is important and is the source of the post-exertional malaise.
Thanks Jackie. Does this correlate at all with Professor Julia Newton’s findings or is it a separate issue please?
Ann
The AMPK pathway is an alternative pathway to the one introduced in the calculations in the Biophysical Chemistry article, but it should also be put into future calculations.