Skip to main content

Advertisement

SpringerLink
Log in

The altered human serum metabolome induced by a marathon

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

Abstract

Introduction

Endurance races have been associated with a substantial amount of adverse effects which could lead to chronic disease and long-term performance impairment. However, little is known about the holistic metabolic changes occurring within the serum metabolome of athletes after the completion of a marathon.

Objectives

Considering this, the aim of this study was to better characterize the acute metabolic changes induced by a marathon.

Methods

Using an untargeted two dimensional gas chromatography time-of-flight mass spectrometry metabolomics approach, pre- and post-marathon serum samples of 31 athletes were analyzed and compared to identify those metabolites varying the most after the marathon perturbation.

Results

Principle component analysis of the comparative groups indicated natural differentiation due to variation in the total metabolite profiles. Elevated concentrations of carbohydrates, fatty acids, tricarboxylic acid cycle intermediates, ketones and reduced concentrations of amino acids indicated a metabolic shift between various fuel substrate systems. Additionally, elevated odd-chain fatty acids and α-hydroxy acids indicated the utilization of α-oxidation and autophagy as alternative energy-producing mechanisms. Adaptations in gut microbe-associated markers were also observed and correlated with the metabolic flexibility of the athlete.

Conclusion

From these results it is evident that a marathon places immense strain on the energy-producing pathways of the athlete, leading to extensive protein degradation, oxidative stress, mammalian target of rapamycin complex 1 inhibition and autophagy. A better understanding of this metabolic shift could provide new insights for optimizing athletic performance, developing more efficient nutrition regimens and identify strategies to improve recovery.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The current analysis is part of a larger study consisting of multiple aims which are being drafted into various manuscripts. Considering this, the datasets generated from this investigation are not publically available, but can be acquired from the corresponding author on reasonable request. The authors declare that all the results included within this study have been presented clearly, honestly and without fabrication, falsification, or inappropriate data manipulation.

References

  • Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, 57, 289–300.

    Google Scholar 

  • Bonasia, D. E., Rosso, F., Cottino, U., & Rossi, R. (2015). Exercise-induced leg pain. Asia-Pacific Journal of Sports Medicine, Arthroscopy, Rehabilitation and Technology, 2, 73–84.

    PubMed  PubMed Central  Google Scholar 

  • Brioche, T., Pagano, A. F., Py, G., & Chopard, A. (2016). Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention. Molecular Aspects of Medicine, 50, 56–87.

    CAS  PubMed  Google Scholar 

  • Bujak, R., Mateo, J., Blanco, I., Izquierdo-Garcia, J. L., Dudzik, D., Markuszewski, M. J., et al. (2016). New biochemical insights into the mechanisms of pulmonary arterial hypertension in humans. PLoS ONE, 11, 1–14.

    Google Scholar 

  • Cahill, G. F., & Vech, R. L. (2003). Ketoacids? Good medicine? American Clinical and Climatological Association, 114, 149–163.

    Google Scholar 

  • Charlton-Menys, V., & Durrington, P. N. (2007). Human cholesterol metabolism and therapeutic molecules. Experimental Physiology, 93, 27–42.

    Google Scholar 

  • Ebner, M. J., Corol, D. I., Havlikova, H., Honour, J. W., & Fry, J. P. (2006). Identification of neuroactive steroids and their precursors and metabolites in adult male rat brain. Endocrinology, 147, 179–190.

    CAS  PubMed  Google Scholar 

  • Eigenvector Reserch. (2016). PLS_Toolbox 8.2.1 (Version 8.2.1). Manson: Eigenvector Reserch Inc.

    Google Scholar 

  • Eisenberg, F., & Parthasarathy, R. (1987) Measurement of biosynthesis of myo-inositol from glucose 6-phosphate. Methods in Enzymology, 141, 127–143.

    CAS  PubMed  Google Scholar 

  • Esterhuizen, K., van der Westhuizen, F. H., & Louw, R. (2017). Metabolomics of mitochondrial disease. Mitochondrion, 35, 97–110.

    CAS  PubMed  Google Scholar 

  • Fernandez, J. A. M., Vida, C. B., & Glahn, V. P. (2000). Zero replacement in compositional data sets. In H. A. L. Kiers, J.-P. Rasson, P. J. F. Groenen & M. Schader (Eds.), Data analysis, classification, and related methods (pp. 155–160). Berlin: Springer.

    Google Scholar 

  • Gall, W. E., Beebe, K., Lawton, K. A., Adam, K. P., Mitchell, M. W., Nakhle, P. J., et al. (2010). Alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE, 5, e10883.

    PubMed  PubMed Central  Google Scholar 

  • Ghoraba, D. A., Mohamed, M. M., & Zaki, O. K. (2014). Screening of diseases associated with abnormal metabolites for evaluation of HPLC in organic aciduria profiling. Egyptian Journal of Medical Human Genetics, 15, 69–78.

    Google Scholar 

  • Guzik, G. P., & Stachowicz, W. (2016). Study on radiation-induced radicals giving rise to stable EPR signal suitable for the detection of irradiation in L-sorbose-containing fruits. Nukleonika, 61, 461–465.

    CAS  Google Scholar 

  • Heaney, L. M., Deighton, K., & Suzuki, T. (2017) Non-targeted metabolomics in sport and exercise science. Journal of Sports Sciences. https://doi.org/10.1080/02640414.2017.1305122

    PubMed  Google Scholar 

  • Holloszy, J. O., & Coyle, E. F. (1984). Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. Journal of Applied Physiology, 56, 831–838.

    CAS  PubMed  Google Scholar 

  • Holm, P. l. I., Ueland, P. M., Kvalheim, G., & Lien, E. A. (2003). Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography–tandem mass spectrometry. Clinical Chemistry, 49, 286–294.

    CAS  PubMed  Google Scholar 

  • Hootman, K. C., Trezzi, J. P., Kraemer, L., Burwell, L. S., Dong, X., Guertin, K. A., et al. (2017) Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults. Proceedings of the National Academy of Sciences, 114, 4233–4240.

    Google Scholar 

  • Howatson, G., McHugh, M. P., Hill, J. A., Brouner, J., Jewell, A. P., van Someren, K. A., et al. (2010). Influence of tart cherry juice on indices of recovery following marathon running. Scandinavian Journal of Medicine and Science in Sports, 20, 843–852.

    CAS  PubMed  Google Scholar 

  • Hu, X., Shi, Y., Zhang, P., Miao, M., Zhang, T., & Jiang, B. (2016). D-Mannose: Properties, production, and applications: An overview. Comprehensive Reviews in Food Science and Food Safety, 15, 773–785.

    Google Scholar 

  • Hu, X., Wu, L., Wang, Y., Song, Y., Mourant, D., Gunawan, R., et al. (2013). Acid-catalyzed conversion of mono- and poly-sugars into platform chemicals: Effects of molecular structure of sugar substrate. Bioresource Technology, 133, 469–474.

    CAS  PubMed  Google Scholar 

  • Jastrzebski, Z., Zychowska, M., Radziminski, L., Konieczna, A., & Kortas, J. (2015). Damage to liver and skeletal muscles in marathon runners during a 100 km run with regard to age and running speed. Journal of Human Kinetics, 45, 93–102.

    PubMed  PubMed Central  Google Scholar 

  • Jenkins, B. J., Seyssel, K., Chiu, S., Pan, P. H., Lin, S. Y., Stanley, E., et al. (2017). Odd chain fatty acids; new insights of the relationship between the gut microbiota, dietary intake, biosynthesis and glucose intolerance. Scientific Reports, 7, 1–8.

    Google Scholar 

  • Jeukendrup, A. E. (2011). Nutrition for endurance sports: Marathon, triathlon, and road cycling. Journal of Sport Science, 29, 91–99.

    Google Scholar 

  • Kishimoto, Y., Williams, M., Moser, H. W., Hignite, C., & Biemann, K. (1973). Branched-chain and odd-numbered fatty acids and aldehydes in the nervous system of a patient with deranged vitamin B12 metabolism. Journal of Lipid Research, 14, 69–77.

    CAS  PubMed  Google Scholar 

  • Kitamura, T., Seki, N., & Kihara, A. (2017). Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum. Proceedings of the National Academy of Science, 114, 1–8.

    Google Scholar 

  • Kondo, N., Ohno, Y., Yamagata, M., Obara, T., Seki, N., Kitamura, T., et al. (2014). Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids. Nature Communications, 5338, 1–11.

    Google Scholar 

  • Korman, S. H., Andresen, B. S., Zeharia, A., Gutman, A., Boneh, A., & Pitt, J. J. (2005). 2-Ethylhydracrylic aciduria in short/branched-chain acyl-CoA dehydrogenase deficiency: Application to diagnosis and implications for the R-pathway of isoleucine oxidation. Clinical Chemistry, 51, 610–617.

    CAS  PubMed  Google Scholar 

  • Kroger, M., Meister, K., & Kava, R. (2006). Low-calorie sweeteners and other sugar substitutes: A review of the safety issues. Comprehensive Reviews in Food Science and Food Safety, 5, 35–47.

    CAS  Google Scholar 

  • Kujala, U. M., Mäkinen, V.-P., Heinonen, I., Soininen, P., Kangas, A. J., Leskinen, T. H., et al. (2013). Long-term leisure-time physical activity and serum metabolome. Circulation, 127, 340–348.

    CAS  PubMed  Google Scholar 

  • Kumar, A., & Bachhawat, A. K. (2012). Pyroglutamic acid: Throwing light on a lightly studied metabolite. Current Science, 102, 288–297.

    CAS  Google Scholar 

  • Kumdam, H., Murthy, S. N., & Gummadi, S. N. (2014). Arabitol production by microbial fermentation—biosynthesis and future applications. International Journal of Sciences and Applied Research, 1, 1–12.

    Google Scholar 

  • Laplante, M., & Sabatini, D. M. (2009). mTOR signaling at a glance. Journal of Cell Science, 122, 3589–3594.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis, G. D., Farrell, L., Wood, M. J., Martinovic, M., Arany, Z., Rowe, G. C., et al. (2010). Metabolic signatures of exercise in human plasma. Science Translational Medicine, 2, 33–37.

    Google Scholar 

  • Liebich, H. M., & Pickert, A. (1985). Gas chromatographic profiling of phenolic acids in urine of patients with cirrhosis of the liver. Journal of Chromatography, 338, 25–32.

    CAS  PubMed  Google Scholar 

  • Lippi, G., Schena, F., Montagnana, M., Salvagno, G. L., Banfi, G., & Guidi, G. C. (2011). Significant variation of traditional markers of liver injury after a half-marathon run. European Journal of Internal Medicine, 22, E36–E38.

    CAS  PubMed  Google Scholar 

  • Luies, L., & Loots, D. T. (2016). Tuberculosis metabolomics reveals adaptations of man and microbe in order to outcompete and survive. Metabolomics, 12, 1–9.

    Google Scholar 

  • Mach, N., & Fuster-Botella, D. (2017). Endurance exercise and gut microbiota: A review. Journal of Sport and Health Science, 6, 179–197.

    PubMed  Google Scholar 

  • MacLaren, D., & Morton, J. (2012). Biochemistry for sport and exercise metabolism (1 ed.). West Sussex: Wiley

    Google Scholar 

  • Maes, M., Smith, R., Christophe, A., Cosyns, P., Desnyder, R., & Meltzer, H. (1996). Fatty acid composition in major depression: Decreased w3 fractions in cholesteryl esters and increased C20:4w6/C20:5w3 ratio in cholesteryl esters and phospholipids. Journal of Affective Disorders, 38, 35–46.

    CAS  PubMed  Google Scholar 

  • MATLAB. (2012). MATLAB and Statistics toolbox (Version 2012b). Natick: The MathWorks Inc.

    Google Scholar 

  • Mcanulty, S. R., Owens, J. T., Mcanulty, L. S., Nieman, D. C., Morrow, J. D., Dumke, C. L., & Milne, G. L. (2007). Ibuprofen use during extreme exercise: Effects on oxidative stress and PGE2. Medicine and Science in Sports and Exercise, 39, 1075–1079.

    CAS  PubMed  Google Scholar 

  • McNutt, K. (2000). What clients need to know about sugar replacers. Journal of the American Dietetic Association, 100, 466–469.

    CAS  PubMed  Google Scholar 

  • Mistou, M. Y., Sutcliffe, I. C., & van Sorge, N. M. (2016). Bacterial glycobiology: Rhamnose-containing cell wall polysaccharides in Gram-positive bacteria. FEMS Microbiol Review, 40, 464–479.

    CAS  Google Scholar 

  • Mock, D. M., Stratton, S. L., Horvath, T. D., Bogusiewicz, A., Matthews, N. I., Henrich, C. L., et al. (2011). Brain, behavior, and immunity urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. Journal of Nutrition, 141, 1925–1930.

    CAS  PubMed  Google Scholar 

  • Nieman, D. C., Henson, D. A., Dumke, C. L., Oley, K., McAnulty, S. R., Davis, J. M., et al. (2006). Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition. Brain, Behavior, and Immunity, 20, 578–584.

    CAS  PubMed  Google Scholar 

  • Ojiambo, R. M. (2013). Physical activity and well-being: A review of the health benefits of physical activity on health outcomes. Journal of Applied Medical Sciences, 2, 69–78.

    Google Scholar 

  • Peake, J. M., Tan, S. J., Markworth, J. F., Broadbent, J. A., Skinner, T. L., & Cameron-Smith, D. (2014). Metabolic and hormonal responses to isoenergetic high-intensity interval exercise and continuous moderate-intensity exercise. American Journal of Pathology, 307, 539–552.

    Google Scholar 

  • Peake, R. W. A. (2016). Seizures, dystonia, and spasms in a 14-year-old child. Clinical Chemistry, 62, 1159–1168.

    CAS  PubMed  Google Scholar 

  • Pechlivanis, A., Kostidis, S., Saraslanidis, P., Petridou, A., Tsalis, G., Mougios, V., et al. (2010). H NMR-based metabonomic investigation of the effect of two different exercise sessions on the metabolic fingerprint of human urine. Journal of Proteome Research, 9, 6405–6416.

    CAS  PubMed  Google Scholar 

  • Pfeiffer, B., Stellingwerff, T., Hodgson, A. B., Randell, R., Pottgen, K., Res, P., et al. (2012). Nutritional intake and gastrointestinal problems during competitive endurance events. Medicine and Science in Sports and Exercise, 44, 344–351.

    CAS  PubMed  Google Scholar 

  • Pfeuffer, M., & Jaudszus, A. (2016). Pentadecanoic and heptadecanoic acids: Multifaceted odd-chain fatty acids. Advances in Nutrition, 7, 730–734.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qiang, F. (2015). Effect of malate-oligosaccharide solution on antioxidant capacity of endurance athletes. The Open Biomedical Engineering Journal, 9, 326–329.

    PubMed  PubMed Central  Google Scholar 

  • Richter, E. A., Turcotte, L., Hespel, P., & Kiens, B. (1992). Metabolic responses to exercise: Effects of endurance training and implications for diabetes. Diabetes Care, 15, 1767–1776.

    CAS  PubMed  Google Scholar 

  • Robson-Ansley, P., Howatson, G., Tallent, J., Mitcheson, K., Walshe, I., Toms, C., et al. (2012). Prevalence of allergy and upper respiratory tract symptoms in runners of the London marathon. Medicine & Science in Sports & Exercise, 44, 999–1004.

    Google Scholar 

  • Roe, C. R., & Ding, J. (2001). Mitochondrial fatty acid oxidation disorders. In The online metabolic and molecular bases of inherited disease. New York: The McGraw-Hill Companies.

    Google Scholar 

  • Rosner, B., Glynn, R. J., & Lee, M.-L. T. (2006). The Wilcoxon signed rank test for paired comparisons of clustered data. Biometrics, 62, 185–192.

    PubMed  Google Scholar 

  • Ryan, R. O. (2015). Metabolic annotation of 2-ethylhydracrylic acid. Clinical Chimica Acta, 448, 91–97.

    CAS  Google Scholar 

  • Salway, J. G. (2012). Medical biochemistry at a glance (3rd ed.). Oxford: Wiley.

    Google Scholar 

  • Simpson, G. L. W., & Ortwerth, B. J. (2000). The non-oxidative degradation of ascorbic acid at physiological conditions. Biochimica et Biophysica Acta, 1501, 12–24.

    CAS  PubMed  Google Scholar 

  • Singh, R., & Cuervo, A. M. (2011). Autophagy in the cellular energetic balance. Cellular Metababolism, 13, 495–504.

    CAS  Google Scholar 

  • Staron, R. S., Hikida, R. S., Murray, T. F., Hagerman, F. C., & Hagerman, M. T. (1989). Lipid depletion and repletion in skeletal muscle following a marathon. Journal of the Neurological Sciences, 94, 29–40.

    CAS  PubMed  Google Scholar 

  • Stellingwerff, T. (2012). Case study: Nutrition and training periodization in three elite marathon runners. International Journal of Sport Nutrition and Exercise Metablism, 22, 392–400.

    Google Scholar 

  • Tomczak, M., & Tomczak, E. (2014). The need to report effect size estimates revisited: An overview of some recommended measures of effect size. Trends in Sport Science, 1, 19–25.

    Google Scholar 

  • Turer, A. T., Lewis, G. D., O’Sullivan, J. F., Elmariah, S., Mega, J. L., Addo, T. A., et al. (2014). Increases in myocardial workload induced by rapid atrial pacing trigger alterations in global metabolism. PLoS ONE, 9, 1–9.

    Google Scholar 

  • Van den Berg, R. A., Hoefsloot, H. C., Westerhuis, J. A., Smilde, A. K., & van der Werf, M. J. (2006). Centering, scaling, and transformations: Improving the biological information content of metabolomics data. BMC Genomics, 7, 142.

    PubMed  PubMed Central  Google Scholar 

  • Wadman, S. K., Duran, M., Ketting, D., Bruinvis, L., De Bree, P. K., Kamerling, J. P., et al. (1976). D-Glyceric acidemia in a patient with chronic metabolic acidosis. Clinica Chimica Acta, 71, 477–484.

    CAS  Google Scholar 

  • Waśkiewicz, Z., Klapcinska, B., Sadowska-Krepa, E., Czuba, M., Kempa, K., Kimsa, E., et al. (2012). Acute metabolic responses to a 24-h ultra-marathon race in male amateur runners. European Journal of Applied Physiology, 112, 1679–1688.

    PubMed  Google Scholar 

  • Webner, D., DuPrey, K. M., Drezner, J. A., Cronholm, P., & Roberts, W. O. (2012). Sudden cardiac arrest and death in United States marathons. Medicine and Science in Sports and Exercise, 44, 1843–1845.

    PubMed  Google Scholar 

  • Wendel, U., Langenbeck, U., & Seakins, J. W. T. (1989). Interrelation between the metabolism of LIsoleucine and L-allo-isoleucine in patients with maple syrup urine disease. Pediatric Research, 25, 11–15.

    CAS  PubMed  Google Scholar 

  • Wikoff, W. R., Anfora, A., Liu, T. J., Schultz, P. G., Lesley, S. A., Peters, E. C., & Siuzdak, G. (2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proceedings of the National Academy of Sciences, 106, 3698–3703.

    CAS  Google Scholar 

  • Żółtaszek, R., Hanausek, M., Kiliańska, Z. M., & Walaszek, Z. (2008). The biological role of D-glucaric acid and its derivatives: Potential use in medicine. Postepy Gigieny i Medycyny Doswiadczalnej, 62, 451–462.

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Mari van Reenen for assistance with statistical analysis, Mrs. Derylize Beukes-Maasdorp for sample analysis and Prof. Nico L. Smit for initiating the collaboration.

Funding

The authors have no specific funding to report.

Author information

Authors and Affiliations

  1. Human Metabolomics, North-West University, Private Bag X6001, Box 269, Potchefstroom, 2531, South Africa

    Zinandré Stander, Laneke Luies, Lodewyk J. Mienie & Du Toit Loots

  2. SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine, Division of Medical Microbiology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Rondebosch, 7700, South Africa

    Laneke Luies

  3. Faculty of Health and Life Sciences, Department of Sport, Exercise and Rehabilitation, Northumbria University, NE1 8ST, Newcastle upon Tyne, UK

    Karen M. Keane, Glyn Howatson & Tom Clifford

  4. Water Research Group, School of Environmental Sciences and Development, North-West University, Potchefstroom, 2531, South Africa

    Glyn Howatson

  5. Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

    Tom Clifford & Emma J. Stevenson

Authors
  1. Zinandré Stander
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laneke Luies
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lodewyk J. Mienie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karen M. Keane
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Glyn Howatson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tom Clifford
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emma J. Stevenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Du Toit Loots
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The concept and study were designed by DTL, ZS, GH, TC, KMK and EJS; samples were acquired from the Northumbria University in collaboration with GH, TC, KMK and EMS. ZS was responsible for manuscript drafting, data analysis and interpretation, the latter of which was assisted by DTL, LL and LJM. LL, LJM and DTL were involved in repeated manuscript reviewing, of which LL was greatly involved with structural (format) editing. All of the authors revised and approved the final version of this manuscript.

Corresponding author

Correspondence to Du Toit Loots.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest, and that this manuscript, and the work described therein, is unpublished and has not been submitted for publication elsewhere.

Ethical approval

Ethical approval for this investigation, conducted according to the Declaration of Helsinki and International Conference on Harmonization Guidelines, was obtained from the Research Ethics Committee of the Faculty of Health and Life Sciences at the Northumbria University in Newcastle upon Tyne, UK (Reference Number: HLSTC120716).

Informed consent

Informed consent was obtained from all individuals included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stander, Z., Luies, L., Mienie, L.J. et al. The altered human serum metabolome induced by a marathon. Metabolomics 14, 150 (2018). https://doi.org/10.1007/s11306-018-1447-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11306-018-1447-4

Keywords

Search

Navigation