Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ME/CFS:

Myalgic encephalomyelitis/chronic fatigue syndrome

PCA:

Principal components analysis

BCAAs:

Branched chain amino acids

AST:

Aspartate transaminase

ROS:

Reactive oxygen species

References

  • 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.

    Article  CAS  Google Scholar 

  • Ax, S., Gregg, V. H., & Jones, D. (2001). Coping and illness cognitions: chronic fatigue syndrome. Clinical Psychology Review, 21(2), 161–182.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brealey, D., & Singer, M. (2009). Hyperglycemia in critical illness: a review. Journal of Diabetes Science and Technology, 3(6), 1250–1260.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Efron, B., & Tibshirani, R. (1993). An introduction to the bootstrap. New York: Chapman & Hall.

    Book  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Johnson, S. K., DeLuca, J., & Natelson, B. H. (1999). Chronic fatigue syndrome: reviewing the research findings. Annals of Behavioral Medicine, 21(3), 258–271.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Meldrum, B. S. (2000). Glutamate as a neurotransmitter in the brain: review of physiology and pathology. Journal of Nutrition, 130(4S Suppl), 1007S–1015S.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

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).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC, 3010, Australia

    Christopher W. Armstrong & Paul R. Gooley

  2. Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne, Parkville, VIC, 3010, Australia

    Neil R. McGregor

  3. CFS Discovery, Donvale Medical Centre, Donvale, VIC, 3111, Australia

    Donald P. Lewis

  4. Bioscreen (Aust) Pty Ltd, 5 Little Hyde St., Yarraville, VIC, 3013, Australia

    Henry L. Butt

Authors
  1. Christopher W. Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil R. McGregor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Donald P. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Henry L. Butt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul R. Gooley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul R. Gooley.

Additional information

Data Deposition

The data for this study has been deposited at MetaboLights (http://www.ebi.ac.uk/metabolights) with accession number MTBLS161.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Armstrong, C.W., McGregor, N.R., Lewis, D.P. et al. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Metabolomics 11, 1626–1639 (2015). https://doi.org/10.1007/s11306-015-0816-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11306-015-0816-5

Keywords

Search

Navigation