TGI Friday! Our weekly round-up of recently published research abstracts | 2 September 2016

From Proceedings of the National Academy of Sciences (accessed 30 August 2016).

Metabolic features of chronic fatigue syndrome

Robert K. Naviaux(a,b,c,d,1), Jane C. Naviaux(a,e), Kefeng Li(a,b), A. Taylor Bright(a,b), William A. Alaynick(a,b), Lin Wang(a,b), Asha Baxter(f), Neil Nathan(f.2), Wayne Anderson(f), and Eric Gordon(f).
a) The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA 92103-8467;
b) Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA 92103-8467;
c) Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, CA 92103-8467;
d) Department of Pathology, University of California, San Diego School of Medicine, San Diego, CA 92103-8467;
e) Department of Neurosciences, University of California, San Diego School of Medicine, San Diego, CA 92103-8467;
f) Gordon Medical Associates, Santa Rosa, CA 95403
Edited by Ronald W. Davis, Stanford University School of Medicine, Stanford, CA, and approved July 13, 2016 (received for review May 11, 2016)


Chronic fatigue syndrome is a multisystem disease that causes long-term pain and disability. It is difficult to diagnose because of its protean symptoms and the lack of a diagnostic laboratory test. We report that targeted, broad-spectrum metabolomics of plasma not only revealed a characteristic chemical signature but also revealed an unexpected underlying biology. Metabolomics showed that chronic fatigue syndrome is a highly concerted hypometabolic response to environmental stress that traces to mitochondria and was similar to the classically studied developmental state of dauer. This discovery opens a fresh path for the rational development of new therapeutics and identifies metabolomics as a powerful tool to identify the chemical differences that contribute to health and disease.


More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS. We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls.

Males with CFS were 53 (±2.8) y old (mean ± SEM; range, 21–67 y). Females were 52 (±2.5) y old (range, 20–67 y). The Karnofsky performance scores were 62 (±3.2) for males and 54 (±3.3) for females.

We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method.

Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism.

Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84–100%] in males using eight metabolites and 96% (95% CI, 86–100%) in females using 13 metabolites.

Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.

From the Journal of Translational Medicine, 31 August 2016.

Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients

Emmanuel Fenouillet, Aude Vigouroux, Jean Guillaume Steinberg, Alexandre Chagvardieff, Frédérique Retornaz, Regis Guieu and Yves Jammes



Myalgic encephalomyelitis chronic fatigue syndrome (ME/CFS) is a common debilitating disorder associated with an intense fatigue, a reduced physical activity, and an impaired quality of life. There are no established biological markerof the syndrome. The etiology is unknown and its pathogenesis appears to be multifactorial. Various stressors, including intense physical activity, severe infection, and emotional stress are reported in the medical history of ME/CFS patients which raises the question whether any physiological and biological abnormalities usually found in these patients could be indicative of the etiology and/or the quality-of-life impairment.


Thirty-six patients and 11 age-matched healthy controls were recruited. The following variables that appear to address common symptoms of ME/CFS were studied here: (1) muscle fatigue during exercise has been investigated by monitoring the compound muscle action potential (M-wave); (2) the excessive oxidative stress response to exercise was measured via two plasma markers (thiobarbituric acid reactive substances: TBARS; reduced ascorbic-acid: RAA); (3) a potential inflammatory component was addressed via expression of CD26 on peripheral blood mononuclear cells; (4) quality-of-life impairment was assessed using the London Handicap Scale (LHS) and the Medical Outcome Study Short Form-36 (SF-36). The medical history of each patient, including the presence of stressors such as intense sports practice, severe acute infection and/or severe emotional stress was documented.


We observed that: (1) there were striking differences between cases and controls with regard to three biological variables: post-exercise M-wave, TBARS variations and CD26-expression at rest; (2) each of these three variables correlated with the other two; (3) abnormalities in the biomarkers associated with health-related quality of life: the LHS score was negatively correlated with the exercise-induced TBARS increase and positively correlated with CD26-expression while the pain component of SF-36 was negatively correlated with CD26-expression; (4) the TBARS increase and the M-wave decrease were the highest, and the CD26-expression level the lowest in patients who had been submitted to infectious stressors.


In ME/CFS patients, severe alterations of the muscle excitability, the redox status, as well as the CD26-expression level are correlated with a marked impairment of the quality-of-life. They are particularly significant when infectious stressors are reported in the medical history.

From The Netherlands Heart Journal, 25 August 2016. [Epub ahead of print].

Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging.

Olimulder MA(1), Galjee MA(1), Wagenaar LJ(1), van Es J(1), van der Palen J(2,3), Visser FC(4), Vermeulen RC(4), von Birgelen C(5,6).
1) Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, The Netherlands.
2) Department of Epidemiology, Medisch Spectrum Twente, Enschede, The Netherlands.
3) Department of Research Methodology, Measurement & Data Analysis, University of Twente, Enschede, The Netherlands.
4) Centre for Chronic Fatigue Syndrome, Amsterdam, The Netherlands.
5) Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, The Netherlands.
6) Department of Health Technology and Services Research, MIRA-Institute for Biomedical Technology & Technical Medicine, University of Twente, Enschede, The Netherlands.



In chronic fatigue syndrome (CFS), only a few imaging and histopathological studies have previously assessed either cardiac dimensions/function or myocardial tissue, suggesting smaller left ventricular (LV) dimensions, LV wall motion abnormalities and occasionally viral persistence that may lead to cardiomyopathy. The present study with cardiac magnetic resonance (CMR) imaging is the first to use a contrast-enhanced approach to assess cardiac involvement, including tissue characterisation of the LV wall.


CMR measurements of 12 female CFS patients were compared with data of 36 age-matched, healthy female controls. With cine imaging, LV volumes, ejection fraction (EF), mass, and wall motion abnormalities were assessed. T2-weighted images were analysed for increased signal intensity, reflecting oedema (i.e. inflammation). In addition, the presence of contrast enhancement, reflecting fibrosis (i.e. myocardial damage), was analysed.


When comparing CFS patients and healthy controls, LVEF (57.9 ± 4.3 % vs. 63.7 ± 3.7 %; p < 0.01), end-diastolic diameter (44 ± 3.7 mm vs. 49 ± 3.7 mm; p < 0.01), as well as body surface area corrected LV end-diastolic volume (77.5 ± 6.2 ml/m2 vs. 86.0 ± 9.3 ml/m2; p < 0.01), stroke volume (44.9 ± 4.5 ml/m2 vs. 54.9 ± 6.3 ml/m2; p < 0.001), and mass (39.8 ± 6.5 g/m2 vs. 49.6 ± 7.1 g/m2; p = 0.02) were significantly lower in patients. Wall motion abnormalities were observed in four patients and contrast enhancement (fibrosis) in three; none of the controls showed wall motion abnormalities or contrast enhancement. None of the patients or controls showed increased signal intensity on the T2-weighted images. CONCLUSION In patients with CFS, CMR demonstrated lower LV dimensions and a mildly reduced LV function. The presence of myocardial fibrosis in some CFS patients suggests that CMR assessment of cardiac involvement is warranted as part of the scientific exploration, which may imply serial non-invasive examinations.


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