, Volume 11, Issue 6, pp 1626–1639 | Cite as

Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients

  • Christopher W. Armstrong
  • Neil R. McGregor
  • Donald P. Lewis
  • Henry L. Butt
  • Paul R. GooleyEmail author
Original Article


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating long-term multisystem disorder with a central and inexplicably persistent fatigue symptom that is unable to be relieved by rest. Energy metabolism and oxidative stress have been recent focal points of ME/CFS research and in this study we were able to elucidate metabolic pathways that were indicative of their dysfunction. Blood and urine samples were collected from 34 females with ME/CFS (34.9 ± 1.8 SE years old) and 25 non-ME/CFS female participants (33.0 ± 1.6 SE years old). All samples underwent metabolic profiling via 1D 1H Nuclear magnetic resonance spectroscopy and quantitated metabolites were assessed for significance. Blood glucose was elevated while blood lactate, urine pyruvate, and urine alanine were reduced indicating an inhibition of glycolysis that may potentially reduce the provision of adequate acetyl-CoA for the citric acid cycle. We propose that amino acids are being increasingly used to provide an adequate carbohydrate source for the citric acid cycle. We suggest that this is via glutamate forming 2-oxoglutarate through an enzyme that deaminates it and subsequently elevates blood aspartate. Dysfunctional energy metabolism appears to have impacted creatinine and its elevation in urine suggests that it may be used as an alternative for anaerobic ATP production within muscle. A decrease in blood hypoxanthine and an increase in urine allantoin further suggest the elevation of reactive oxygen species in ME/CFS patients. These findings bring new information to the research of energy metabolism, chronic immune activation and oxidative stress issues within ME/CFS.


Chronic fatigue syndrome Metabolic Blood Urine Oxidative Stress Energy metabolism Amino Acids 



Myalgic encephalomyelitis/chronic fatigue syndrome


Principal components analysis


Branched chain amino acids


Aspartate transaminase


Reactive oxygen species



The authors of this work would like to thank the nursing and administrative staff at the CFS Discovery clinic for their important help throughout this study. This work was supported by grants from the Judith Jane Mason & Harold Stannett Williams Memorial Foundation (The Mason Foundation) and equipment grants from the Rowden White foundation and State of Victoria.

Conflict of interest

There were no conflict of interest.

Compliance with ethical requirements

This study was approved by the University of Melbourne human research ethics committee (HREC# 0723086).


  1. Armstrong, C. W., McGregor, N. R., Sheedy, J. R., Buttfield, I., Butt, H. L., & Gooley, P. R. (2012). NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. Clinica Chimica Acta, 413(19–20), 1525–1531. doi: 10.1016/j.cca.2012.06.022.CrossRefGoogle Scholar
  2. Ax, S., Gregg, V. H., & Jones, D. (2001). Coping and illness cognitions: chronic fatigue syndrome. Clinical Psychology Review, 21(2), 161–182.CrossRefPubMedGoogle Scholar
  3. Booth, N. E., Myhill, S., & McLaren-Howard, J. (2012). Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). International Journal of Clinical and Experimental Medicine, 5(3), 208–220.PubMedPubMedCentralGoogle Scholar
  4. Brealey, D., & Singer, M. (2009). Hyperglycemia in critical illness: a review. Journal of Diabetes Science and Technology, 3(6), 1250–1260.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Buchwald, D., Ashley, R. L., Pearlman, T., Kith, P., & Komaroff, A. L. (1996). Viral serologies in patients with chronic fatigue and chronic fatigue syndrome. Journal of Medical Virology, 50(1), 25–30. doi: 10.1002/(SICI)1096-9071(199609)50:1<25:AID-JMV6>3.0.CO;2-V.CrossRefPubMedGoogle Scholar
  6. Cabrera, O., Jacques-Silva, M. C., Speier, S., Yang, S. N., Kohler, M., Fachado, A., et al. (2008). Glutamate is a positive autocrine signal for glucagon release. Cell Metabolism, 7(6), 545–554. doi: 10.1016/j.cmet.2008.03.004.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Candy, B., Chalder, T., Cleare, A. J., Wessely, S., & Hotopf, M. (2004). A randomised controlled trial of a psycho-educational intervention to aid recovery in infectious mononucleosis. Journal of Psychosomatic Research, 57(1), 89–94. doi: 10.1016/S0022-3999(03)00370-2.CrossRefPubMedGoogle Scholar
  8. Candy, B., Chalder, T., Cleare, A. J., Wessely, S., White, P. D., & Hotopf, M. (2002). Recovery from infectious mononucleosis: a case for more than symptomatic therapy? a systematic review. British Journal of General Practice, 52(483), 844–851.PubMedPubMedCentralGoogle Scholar
  9. Cao, M., George, T. J., Prima, V., Nelson, D., & Svetlov, S. (2013). Argininosuccinate synthase as a novel biomarker for inflammatory conditions. Biomarkers, 18(3), 242–249. doi: 10.3109/1354750X.2013.773080.CrossRefPubMedGoogle Scholar
  10. Carruthers, B. M. (2007). Definitions and aetiology of myalgic encephalomyelitis: how the Canadian consensus clinical definition of myalgic encephalomyelitis works. Journal of Clinical Pathology, 60(2), 117–119. doi: 10.1136/jcp.2006.042754.CrossRefPubMedGoogle Scholar
  11. Carruthers, B. M., Jain, A. K., De Meirleir, K. L., Peterson, D. L., Klimas, N. G., Lerner, A. M., et al. (2003). Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. Journal of Chronic Fatigue Syndrome, 11(1), 7–36.CrossRefGoogle Scholar
  12. Carruthers, B. M., van de Sande, M. I., De Meirleir, K. L., Klimas, N. G., Broderick, G., Mitchell, T., et al. (2011). Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine, 270(4), 327–338. doi: 10.1111/j.1365-2796.2011.02428.x.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Christley, Y., Duffy, T., & Martin, C. R. (2012). A review of the definitional criteria for chronic fatigue syndrome. Journal of Evaluation in Clinical Practice, 18(1), 25–31. doi: 10.1111/j.1365-2753.2010.01512.x.CrossRefPubMedGoogle Scholar
  14. Efron, B., & Tibshirani, R. (1993). An introduction to the bootstrap. New York: Chapman & Hall.CrossRefGoogle Scholar
  15. Fahien, L. A., & Macdonald, M. J. (2011). The complex mechanism of glutamate dehydrogenase in insulin secretion. Diabetes, 60(10), 2450–2454. doi: 10.2337/db10-1150.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Filler, K., Lyon, D., Bennett, J., McCain, N., Elswick, R., Lukkahatai, N., et al. (2014). Association of mitochondrial dysfunction and fatigue: a review of the literature. BBA Clinical, 1, 12–23. doi: 10.1016/j.bbacli.2014.04.001.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fukuda, K., Straus, S. E., Hickie, I., Sharpe, M. C., Dobbins, J. G., & Komaroff, A. (1994). The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Annals of Internal Medicine, 121(12), 953–959.CrossRefPubMedGoogle Scholar
  18. Georgiades, E., Behan, W. M. H., Kilduff, L. P., Hadjicharalambous, M., Mackie, E. E., Wilson, J., et al. (2003). Chronic fatigue syndrome: new evidence for a central fatigue disorder. Clinical Science, 105(2), 213–218.CrossRefPubMedGoogle Scholar
  19. Holmes, G. P., Kaplan, J. E., Gantz, N. M., Komaroff, A. L., Schonberger, L. B., Straus, S. E., et al. (1988). Chronic fatigue syndrome: a working case definition. Annals of Internal Medicine, 108(3), 387–389.CrossRefPubMedGoogle Scholar
  20. Husson, A., Brasse-Lagnel, C., Fairand, A., Renouf, S., & Lavoinne, A. (2003). Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. European Journal of Biochemistry, 270(9), 1887–1899.CrossRefPubMedGoogle Scholar
  21. Jason, L. A., Richman, J. A., Rademaker, A. W., Jordan, K. M., Plioplys, A. V., Taylor, R. R., et al. (1999). A community-based study of chronic fatigue syndrome. Archives of Internal Medicine, 159(18), 2129–2137.CrossRefPubMedGoogle Scholar
  22. Johnson, S. K., DeLuca, J., & Natelson, B. H. (1999). Chronic fatigue syndrome: reviewing the research findings. Annals of Behavioral Medicine, 21(3), 258–271.CrossRefPubMedGoogle Scholar
  23. Jones, M. G., Cooper, E., Amjad, S., Goodwin, C. S., Barron, J. L., & Chalmers, R. A. (2005). Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. Clinica Chimica Acta, 361(1–2), 150–158. doi: 10.1016/j.cccn.2005.05.023.CrossRefGoogle Scholar
  24. Kennedy, G., Spence, V. A., McLaren, M., Hill, A., Underwood, C., & Belch, J. J. (2005). Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radical Biology and Medicine, 39(5), 584–589. doi: 10.1016/j.freeradbiomed.2005.04.020.CrossRefPubMedGoogle Scholar
  25. Maes, M. (2009). Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Current Opinion in Psychiatry, 22(1), 75–83.CrossRefPubMedGoogle Scholar
  26. McGregor, N. R., Dunstan, R. H., Zerbes, M., Butt, H. L., Roberts, T. K., & Klineberg, I. J. (1996). Preliminary determination of a molecular basis to chronic fatigue syndrome. Biochemical and Molecular Medicine, 57(2), 73–80.CrossRefPubMedGoogle Scholar
  27. Meeus, M., Nijs, J., Hermans, L., Goubert, D., & Calders, P. (2013). The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opinion on Therapeutic Targets, 17(9), 1081–1089. doi: 10.1517/14728222.2013.818657.CrossRefPubMedGoogle Scholar
  28. Meldrum, B. S. (2000). Glutamate as a neurotransmitter in the brain: review of physiology and pathology. Journal of Nutrition, 130(4S Suppl), 1007S–1015S.PubMedGoogle Scholar
  29. Mikami, T., Kita, K., Tomita, S., Qu, G. J., Tasaki, Y., & Ito, A. (2000). Is allantoin in serum and urine a useful indicator of exercise-induced oxidative stress in humans? Free Radical Research, 32(3), 235–244.CrossRefPubMedGoogle Scholar
  30. Maes, M., Kubera, M., Uytterhoeven, M., Vrydags, N., & Bosmans, E. (2011). Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Medical Science Monitor, 17(4), SC11–SC15.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Morris, G., & Maes, M. (2014a). Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metabolic Brain Disease, 29(1), 19–36. doi: 10.1007/s11011-013-9435-x.CrossRefPubMedGoogle Scholar
  32. Morris, G., & Maes, M. (2014b). Oxidative and nitrosative stress and immune-inflammatory pathways in patients with myalgic encephalomyelitis (me)/chronic fatigue syndrome (cfs). Current Neuropharmacology, 12(2), 168–185. doi: 10.2174/1570159X11666131120224653.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Niblett, S. H., King, K. E., Dunstan, R. H., Clifton-Bligh, P., Hoskin, L. A., Roberts, T. K., et al. (2007). Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome. Experimental Biology and Medicine (Maywood), 232(8), 1041–1049. doi: 10.3181/0702-RM-44.CrossRefGoogle Scholar
  34. Ortega-Hernandez, O. D., & Shoenfeld, Y. (2009). Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Annals of the New York Academy of Sciences, 1173, 600–609. doi: 10.1111/j.1749-6632.2009.04799.x.CrossRefPubMedGoogle Scholar
  35. Robinson, L. E., & van Soeren, M. H. (2004). Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control. AACN Clinical Issues, 15(1), 45–62.CrossRefPubMedGoogle Scholar
  36. Serkova, N., Fuller, T. F., Klawitter, J., Freise, C. E., & Niemann, C. U. (2005). 1H-NMR-based metabolic signatures of mild and severe ischemia/reperfusion injury in rat kidney transplants. Kidney International, 67(3), 1142–1151. doi: 10.1111/j.1523-1755.2005.00181.x.CrossRefPubMedGoogle Scholar
  37. Sheedy, J. R., Ebeling, P. R., Gooley, P. R., & McConville, M. J. (2010). A sample preparation protocol for 1H nuclear magnetic resonance studies of water-soluble metabolites in blood and urine. Analytical Biochemistry, 398(2), 263–265. doi: 10.1016/j.ab.2009.11.027.CrossRefPubMedGoogle Scholar
  38. Shungu, D. C., Weiduschat, N., Murrough, J. W., Mao, X., Pillemer, S., Dyke, J. P., et al. (2012). Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR in Biomedicine, 25(9), 1073–1087. doi: 10.1002/nbm.2772.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Smits, B., van den Heuvel, L., Knoop, H., Kusters, B., Janssen, A., Borm, G., et al. (2011). Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome. Mitochondrion, 11(5), 735–738. doi: 10.1016/j.mito.2011.05.005.CrossRefPubMedGoogle Scholar
  40. Snell, C. R., Stevens, S. R., Davenport, T. E., & Van Ness, J. M. (2013). Discriminative validity of metabolic and workload measurements for identifying people with chronic fatigue syndrome. Physical Therapy, 93(11), 1484–1492. doi: 10.2522/ptj.20110368.CrossRefPubMedGoogle Scholar
  41. Suarez, A., Guillamo, E., Roig, T., Blazquez, A., Alegre, J., Bermudez, J., et al. (2010). Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study. Journal of Womens Health, 19(6), 1073–1077. doi: 10.1089/jwh.2008.1255.CrossRefGoogle Scholar
  42. White, A. T., Light, A. R., Hughen, R. W., Bateman, L., Martins, T. B., Hill, H. R., et al. (2010). Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology, 47(4), 615–624. doi: 10.1111/j.1469-8986.2010.00978.x.PubMedPubMedCentralGoogle Scholar
  43. White, A. T., Light, A. R., Hughen, R. W., Vanhaitsma, T. A., & Light, K. C. (2012). Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. Psychosomatic Medicine, 74(1), 46–54. doi: 10.1097/PSY.0b013e31824152ed.CrossRefPubMedGoogle Scholar
  44. Xiu, F., Stanojcic, M., Diao, L., & Jeschke, M. G. (2014). Stress hyperglycemia, insulin treatment, and innate immune cells. International Journal of Endocrinology, 2014, 486403. doi: 10.1155/2014/486403.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Yu, T., Robotham, J. L., & Yoon, Y. (2006). Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America, 103(8), 2653–2658. doi: 10.1073/pnas.0511154103.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Christopher W. Armstrong
    • 1
  • Neil R. McGregor
    • 2
  • Donald P. Lewis
    • 3
  • Henry L. Butt
    • 4
  • Paul R. Gooley
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology InstituteUniversity of MelbourneParkvilleAustralia
  2. 2.Faculty of Medicine, Dentistry & Health SciencesUniversity of MelbourneParkvilleAustralia
  3. 3.CFS Discovery, Donvale Medical CentreDonvaleAustralia
  4. 4.Bioscreen (Aust) Pty LtdYarravilleAustralia

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