Assessment of Cellular Bioenergetics in Chronic Fatigue Syndrome

Introduction: Abnormalities in bioenergetic function have been cited as one possible cause for chronic fatigue syndrome (CFS). One hypothesis to explain this suggests that CFS may be caused, at least in part, by an acquired mitochondrial dysfunction.

Extracellular flux analysers make real-time, in vitro assessment of cellular energy pathways possible. Using this technology, mitochondrial function can be measured in a variety of cell types in real-time thus increasing our understanding of the role of metabolism in CFS.

Objectives: This project aims to utilise extracellular flux detection technology in order to investigate the cellular bioenergetics of different cell types obtained from CFS patients and healthy controls.

Methods: Mitochondrial stress tests were conducted using skeletal muscle cells and peripheral blood mononuclear cells (PBMCs) derived from CFS patients and controls. During this test mitochondrial complexes are inhibited in turn to modulate respiration so mitochondrial function can be evaluated. The oxygen consumption rate of cells is measured which allows keys parameters of mitochondrial function to be measured and calculated in a single experiment, providing an overall assessment of mitochondrial function. Parameters measured are: basal respiration, maximal respiration and non-mitochondrial respiration. Proton leak, ATP-production and spare respiratory capacity are subsequently able to be calculated using the three measured parameters. CFS patients whose samples were used in these studies were diagnosed using the Fukuda definition.

Results: Results using skeletal muscle cells obtained from CFS patients (n=3) and controls (n=5), indicate that there is no difference in the energy profiles of the skeletal muscle cells of CFS patients in any of the parameters investigated.

Mitochondrial stress test results using PBMCs show CFS PBMCs (n=7) to be significantly lower than control cells (n=10) in all parameters investigated (p≤0.016). Importantly, these results suggest that CFS PBMCs perform closer to their maximum under normal conditions. This means that when CFS PBMCs come under stress they are less able to increase their respiration rate to compensate for the increase in stress.

Conclusions: These findings provide an interesting starting point for investigations into cellular bioenergetics in CFS.

Cara Jasmine Tomas; First year medical science PhD student; Institute of Cellular Medicine, Level 1, William Leech Building, Medical School, Newcastle University, Newcastle Upon-Tyne, NE2 4HH, England; c.j.tomas@ncl.ac.uk
This work was funded by the Medical Research Council and Newcastle University.

 

Source: Cara Tomas, Julia Newton, Audrey Brown, Gina Rutherford, Philip Manning
Newcastle University, UK. Assessment of Cellular Bioenergetics in Chronic Fatigue Syndrome. Poster presentation, IACFS/ME 2016 conference.

Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States

Abstract:

BACKGROUND: XMRV, a xenotropic murine leukemia virus (MuLV)-related virus, was recently identified by PCR testing in 67% of persons with chronic fatigue syndrome (CFS) and in 3.7% of healthy persons from the United States. To investigate the association of XMRV with CFS we tested blood specimens from 51 persons with CFS and 56 healthy persons from the US for evidence of XMRV infection by using serologic and molecular assays. Blinded PCR and serologic testing were performed at the US Centers for Disease Control and Prevention (CDC) and at two additional laboratories.

RESULTS: Archived blood specimens were tested from persons with CFS defined by the 1994 international research case definition and matched healthy controls from Wichita, Kansas and metropolitan, urban, and rural Georgia populations. Serologic testing at CDC utilized a Western blot (WB) assay that showed excellent sensitivity to MuLV and XMRV polyclonal or monoclonal antibodies, and no reactivity on sera from 121 US blood donors or 26 HTLV-and HIV-infected sera. Plasma from 51 CFS cases and plasma from 53 controls were all WB negative. Additional blinded screening of the 51 cases and 53 controls at the Robert Koch Institute using an ELISA employing recombinant Gag and Env XMRV proteins identified weak seroreactivity in one CFS case and a healthy control, which was not confirmed by immunofluorescence. PCR testing at CDC employed a gag and a pol nested PCR assay with a detection threshold of 10 copies in 1 ug of human DNA. DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative. Blinded testing by a second nested gag PCR assay at the Blood Systems Research Institute was also negative for DNA specimens from the 50 CFS cases and 56 controls.

CONCLUSIONS: We did not find any evidence of infection with XMRV in our U.S. study population of CFS patients or healthy controls by using multiple molecular and serologic assays. These data do not support an association of XMRV with CFS.

 

Source: Switzer WM, Jia H, Hohn O, Zheng H, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, Reeves WC, Heneine W. Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States. Retrovirology. 2010 Jul 1;7:57. doi: 10.1186/1742-4690-7-57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908559/ (Full article)

 

Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: To explore contexts of experiences of physical activity perceived as beneficial or harmful for CFS patients.

METHODS: A qualitative study with empirical data from two focus groups with purposive sampling. Mean age was 50, two of ten participants were male, and social demographics varied. Participants were invited to share stories of good as well as bad experiences concerning physical activity. Data were analysed with systematic text condensation.

RESULTS: Participants were not averse to physical activity, but specific preconditions would determine how the activity was perceived. Physical activity was experienced as helpful and enjoyable, especially related to leisure activities where flexible and individual adaptation was feasible. Non-customized activity may precipitate set-backs giving patients the impression of losing control and being betrayed by their bodies. Strategies to review energy usage in daily life could adjust expectations, diminish stress load and assist in approaching a more appropriate priority and balance.

CONCLUSION: Self-management, body awareness and physical activity of choice combined with facilitation and advice from health care professionals is essential to achieve a positive outcome.

PRACTICE IMPLICATIONS: Exercise programmes should be adapted, paced, and self-managed in accordance with personal preferences and activity levels to be beneficial and empowering for CFS patients.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

 

Source: Larun L, Malterud K. Finding the right balance of physical activity: a focus group study about experiences among patients with chronic fatigue syndrome. Patient Educ Couns. 2011 May;83(2):222-6. doi: 10.1016/j.pec.2010.05.027. Epub 2010 Jun 26. https://www.ncbi.nlm.nih.gov/pubmed/20580520

 

The PRIME project: developing a patient evidence-base

Abstract:

BACKGROUND: The concept of evidence has become firmly rooted in health care, with most importance placed on the outcome of research in clinical and economic spheres. Much less emphasis is placed on the patient’s contribution to evidence which remains relatively vague, of low status and often difficult to integrate with other forms of knowledge.

AIM: This article proposes a concept of patient-based evidence, to complement clinical and economic forms of evidence, and demonstrates one way in which it has been operationalized. The PRIME project developed a patient evidence-base to capture the lived experience of individuals with myalgic encephalitis (ME) or chronic fatigue syndrome (CFS).

DESIGN: Interviews were performed with 40 individuals with ME/CFS who varied in a range of demographic characteristics, including age, gender, and how severely affected individuals were.

RESULTS: PRIME has developed a patient evidence-base which has an extensive array of experiences data to provide researchers, clinicians and others with an in-depth insight into the lived experience of ME/CFS that can be used and analysed. Data are grouped into a wide range of themes, which can be downloaded and used in a variety of ways as a source of evidence to enable understanding of the lived experience of ME/CFS and so contribute to the development of a more patient-focused research agenda in ME/CFS.

CONCLUSIONS: While patient-based evidence used in the PRIME Project provides a useful start, further work is required to develop this area conceptually and methodologically, particularly in relation to how patient-based evidence can be considered alongside clinical and economic evidence.

 

Source: Staniszewska S, Crowe S, Badenoch D, Edwards C, Savage J, Norman W. The PRIME project: developing a patient evidence-base. Health Expect. 2010 Sep;13(3):312-22. doi: 10.1111/j.1369-7625.2010.00590.x. Epub 2010 Jun 23. https://www.ncbi.nlm.nih.gov/pubmed/20579119

 

Effect of electroacupuncture at Shenshu (BL 23) and Zusanli (ST 36) on the event-related potentials of chronic fatigue syndrome

Abstract:

OBJECTIVE: To observe the effective mechanism of electroacupuncture for chronic fatigue syndrome (CFS).

METHODS: The dynamic detection of chronobiology was used to test the event-related potentials in 20 healthy subjects and 20 CFS patients. P3a and P3b latencies at 4 equidistant time points (8:00, 14:00, 20:00, 2:00) within 24 hours were collected and analyzed.

RESULTS: (1) Latency of P3a in CFS group was obviously prolonged at 14:00 compared to health group with statistical significance (P < 0.05), latency of P3b was decreased at 14:00 after electroacupuncture treatment with statistical significance compared to that of pre-treatment (P < 0.01). (2) There were obviously circadian rhythm in latency of P3a and P3b in health group (P < 0.05), which were not seen in CFS group (P > 0.05); the circadian rhythm latency of P3b restored after treatment (P < 0.05). (3) The latency acrophase of P3a and P3b pre-treatment obviously shifted backward compared to that of healthy subjects (P < 0.05), shifted forward after electroacupuncture treatment (P < 0.05).

CONCLUSION: The event-related potential circadian rhythms are lost in CFS patients. Electroacupuncture at Shenshu (BL 23) and Zusanli (ST 36) can regulate the circadian rhythm of P3a and P3b latency and improve the cognition of the patients in daytime.

 

Source: Cheng CS, Zhu YH, Liang FR, Wu X, Jin SG, Wu FP. Effect of electroacupuncture at Shenshu (BL 23) and Zusanli (ST 36) on the event-related potentials of chronic fatigue syndrome. Zhongguo Zhen Jiu. 2010 Apr;30(4):309-12. [Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/20568438

 

Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways

Abstract:

BACKGROUND: In a recently published paper, Harvey and Wessely put forward a ‘biopsychosocial’ explanatory model for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is proposed to be applicable to (chronic) fatigue even when apparent medical causes are present.

METHODS: Here, we review the model proposed by Harvey and Wessely, which is the rationale for behaviourally oriented interventions, such as cognitive behaviour therapy (CBT) and graded exercise therapy (GET), and compare this model with a biological model, in which inflammatory, immune, oxidative and nitrosative (IO&NS) pathways are key elements.

DISCUSSION: Although human and animal studies have established that the pathophysiology of ME/CFS includes IO&NS pathways, these abnormalities are not included in the model proposed by Harvey and Wessely. Activation of IO&NS pathways is known to induce fatigue and somatic (F&S) symptoms and can be induced or maintained by viral and bacterial infections, physical and psychosocial stressors, or organic disorders such as (auto)immune disorders. Studies have shown that ME/CFS and major depression are both clinical manifestations of shared IO&NS pathways, and that both disorders can be discriminated by specific symptoms and unshared or differentiating pathways. Interventions with CBT/GET are potentially harmful for many patients with ME/CFS, since the underlying pathophysiological abnormalities may be intensified by physical stressors.

CONCLUSIONS: In contrast to Harvey and Wessely’s (bio)psychosocial model for ME/CFS a bio(psychosocial) model based upon IO&NS abnormalities is likely more appropriate to this complex disorder. In clinical practice, we suggest physicians should also explore the IO&NS pathophysiology by applying laboratory tests that examine the pathways involved.

 

Source: Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010 Jun 15;8:35. doi: 10.1186/1741-7015-8-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901228/ (Full article)

 

Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and its attenuation by olive extract

Abstract:

Various putative theories involved in the development of chronic fatigue syndrome revolve around the role of stress, infection and oxidative stress. Scientific evidence highlighting the protective role of nutritional supplements in chronic fatigue syndrome is lacking.

Based on these assumptions, the present study was designed to evaluate the effect of olive extract in a mouse model of immunologically-induced fatigue, wherein purified lipopolysaccharide (LPS) and Brucella abortus (BA) antigen were used as immunogens. The assessment of chronic fatigue syndrome was based on immobility period during chronic water-immersion stress test for 10 min daily. The stress-induced hyperalgesia was measured by tail withdrawal latency.

Mice challenged with LPS or BA for 19 days showed significant increase in the immobility time, hyperalgesia and oxidative stress on the 19th day. Serum tumor necrosis factor-alpha (TNF-α) levels were also markedly increased with LPS or BA challenge.

Concurrent treatment with olive extract resulted in a significant decrease in the immobility time as well as hyperalgesia. There was significant attenuation of oxidative stress as well as serum TNF-α levels. The results of the present study strongly indicate the role of oxidative stress and immunological activation in the pathophysiology of chronic fatigue syndrome and highlight the valuable role of olive extract in combating chronic fatigue syndrome.

Copyright © 2010 Elsevier B.V. All rights reserved.

 

Source: Gupta A, Vij G, Chopra K. Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and its attenuation by olive extract. J Neuroimmunol. 2010 Sep 14;226(1-2):3-7. doi: 10.1016/j.jneuroim.2010.05.021. Epub 2010 May 26. https://www.ncbi.nlm.nih.gov/pubmed/20537729

 

Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: implications for management

Abstract:

OBJECTIVES: To establish the relationship between the functional impairment experienced by Chronic fatigue syndrome (CFS) patients and the symptoms frequently experienced by those with CFS; specifically cognitive impairment, fatigue and orthostatic symptoms.

DESIGN: Cross sectional questionnaire survey.

SETTING: Specialist CFS Clinical Service.

SUBJECTS: Ninety-nine Fukuda diagnosed CFS and 64-matched controls.

MAIN OUTCOME MEASURES: Symptom and functional assessment tools completed and returned by post included; PROMIS HAQ (Patient-Reported Outcomes Measurement Information System, Health Assessment Questionnaire), CFQ (Cognitive Failures Questionnaire), FIS (Fatigue Impact Scale) and OGS (Orthostatic Grading Scale) assessment tools.

RESULTS: CFS patients experience greater functional impairment than controls [mean (95% CI) PROMIS HAQ scores CFS 36 (31-42) vs. controls 6 (2-10); P < 0.0001], especially in the functional domains of activities and reach. Poorer functional ability impairment is significantly associated with greater cognitive impairment (P = 0.0002, r = 0.4), fatigue (P < 0.0001, r = 0.5) and orthostatic symptoms (P < 0.0001, r = 0.6). However, only orthostatic symptoms (OGS) independently associated with functional impairment (beta = 0.4, P = 0.01).

CONCLUSION: Treatment of orthostatic symptoms in CFS has the potential to improve functional capacity and so improve quality of life.

 

Source: Costigan A, Elliott C, McDonald C, Newton JL. Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: implications for management. QJM. 2010 Aug;103(8):589-95. doi: 10.1093/qjmed/hcq094. Epub 2010 Jun 9. http://qjmed.oxfordjournals.org/content/103/8/589.long (Full article)

 

Illness duration and coping style in chronic fatigue syndrome

Abstract:

A sample of patients with chronic fatigue syndrome was recruited to assess coping strategies and illness duration. It was hypothesized that adaptive coping strategies would be higher among those with longer illness duration.

Those in the longer illness duration group reported higher use of active coping, positive reframing, planning, and acceptance, and lower use of behavioral disengagement than those in the shorter illness duration group. No significant differences were found between the two illness duration groups for physical impairment or symptom severity, but the long duration group revealed a lower percentage of participants who were working than the short duration group.

These findings suggest that individuals with longer or shorter duration of the illness have differences in coping styles but not differences in physical impairment or symptom severity.

 

Source: Brown MM, Brown AA, Jason LA. Illness duration and coping style in chronic fatigue syndrome. Psychol Rep. 2010 Apr;106(2):383-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036543/ (Full article)

 

Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) studies from our laboratory and others described decreased natural killer cell cytotoxicity (NKCC) and elevated proportion of lymphocytes expressing the activation marker, dipeptidyl peptidase IV (DPPIV) also known as CD26. However, neither these assays nor other laboratory tests are widely accepted for the diagnosis or prognosis of CFS. This study sought to determine if NKCC or DPPIV/CD26 have diagnostic accuracy for CFS.

METHODS/RESULTS: Subjects included female and male CFS cases and healthy controls. NK cell function was measured with a bioassay, using K562 cells and (51)Cr release. Lymphocyte associated DPPIV/CD26 was assayed by qualitative and quantitative flow cytometry. Serum DPPIV/CD26 was measured by ELISA. Analysis by receiver operating characteristic (ROC) curve assessed biomarker potential. Cytotoxic function of NK cells for 176 CFS subjects was significantly lower than in the 230 controls. According to ROC analysis, NKCC was a good predictor of CFS status. There was no significant difference in NK cell counts between cases and controls. Percent CD2+ lymphocytes (T cells and NK cells) positive for DPPIV/C26 was elevated in CFS cases, but there was a decrease in the number of molecules (rMol) of DPPIV/C26 expressed on T cells and NK cells and a decrease in the soluble form of the enzyme in serum. Analyses by ROC curves indicated that all three measurements of DPPIV/CD26 demonstrated potential as biomarkers for CFS. None of the DPPIV/C26 assays were significantly correlated with NKCC.

CONCLUSIONS: By ROC analysis, NKCC and three methods of measuring DPPIV/C26 examined in this study had potential as biomarkers for CFS. Of these, NKCC, %CD2+CD26+ lymphocytes and rMol CD26/CD2+ lymphocyte, required flow cytometry, fresh blood and access to a high complexity laboratory. Soluble DPPIV/C26 in serum is done with a standard ELISA assay, or with other soluble factors in a multiplex type of ELISA. Dipeptidyl peptidase IV on lymphocytes or in serum was not predictive of NKCC suggesting that these should be considered as non-redundant biomarkers. Abnormalities in DPPIV/CD26 and in NK cell function have particular relevance to the possible role of infection in the initiation and/or the persistence of CFS.

 

Source: Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, Broderick G, Klimas NG. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS One. 2010 May 25;5(5):e10817. doi: 10.1371/journal.pone.0010817. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876037/ (Full article)