Potential biomarkers of fatigue identified by plasma metabolome analysis in rats

Satoshi Kume, Masanori Yamato, Yasuhisa Tamura, Guanghua Jin, Masayuki Nakano, Yukiharu Miyashige, Asami Eguchi, Yoshiyuki Ogata, Nobuhito Goda, Kazuhiro Iwai, Emi Yamano, Yasuyoshi Watanabe, Tomoyoshi Soga, Yosky Kataoka

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

In the present study, prior to the establishment of a method for the clinical diagnosis of chronic fatigue in humans, we validated the utility of plasma metabolomic analysis in a rat model of fatigue using capillary electrophoresis-mass spectrometry (CE-MS). In order to obtain a fatigued animal group, rats were placed in a cage filled with water to a height of 2.2 cm for 5 days. A food-restricted group, in which rats were limited to 10 g/d of food (around 50% of the control group), was also assessed. The food-restricted group exhibited weight reduction similar to that of the fatigued group. CE-MS measurements were performed to evaluate the profile of food intake-dependent metabolic changes, as well as the profile in fatigue loading, resulting in the identification of 48 metabolites in plasma. Multivariate analyses using hierarchical clustering and principal component analysis revealed that the plasma metabolome in the fatigued group showed clear differences from those in the control and food-restricted groups. In the fatigued group, we found distinctive changes in metabolites related to branched-chain amino acid metabolism, urea cycle, and proline metabolism. Specifically, the fatigued group exhibited significant increases in valine, leucine, isoleucine, and 2-oxoisopentanoate, and significant decreases in citrulline and hydroxyproline compared with the control and food-restricted groups. Plasma levels of total nitric oxide were increased in the fatigued group, indicating systemic oxidative stress. Further, plasma metabolites involved in the citrate cycle, such as cis-aconitate and isocitrate, were reduced in the fatigued group. The levels of ATP were significantly decreased in the liver and skeletal muscle, indicative of a deterioration in energy metabolism in these organs. Thus, this comprehensive metabolic analysis furthered our understanding of the pathophysiology of fatigue, and identified potential diagnostic biomarkers based on fatigue pathophysiology.

Original languageEnglish
Article numbere0120106
JournalPLoS One
Volume10
Issue number3
DOIs
Publication statusPublished - 2015 Mar 20

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Metabolome
metabolomics
Biomarkers
Fatigue
Rats
biomarkers
capillary electrophoresis
Fatigue of materials
metabolites
pathophysiology
Plasmas
Food
rats
Metabolites
mass spectrometry
Capillary Electrophoresis
metabolome
citrulline
Capillary electrophoresis
branched chain amino acids

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kume, S., Yamato, M., Tamura, Y., Jin, G., Nakano, M., Miyashige, Y., ... Kataoka, Y. (2015). Potential biomarkers of fatigue identified by plasma metabolome analysis in rats. PLoS One, 10(3), [e0120106]. https://doi.org/10.1371/journal.pone.0120106

Potential biomarkers of fatigue identified by plasma metabolome analysis in rats. / Kume, Satoshi; Yamato, Masanori; Tamura, Yasuhisa; Jin, Guanghua; Nakano, Masayuki; Miyashige, Yukiharu; Eguchi, Asami; Ogata, Yoshiyuki; Goda, Nobuhito; Iwai, Kazuhiro; Yamano, Emi; Watanabe, Yasuyoshi; Soga, Tomoyoshi; Kataoka, Yosky.

In: PLoS One, Vol. 10, No. 3, e0120106, 20.03.2015.

Research output: Contribution to journalArticle

Kume, S, Yamato, M, Tamura, Y, Jin, G, Nakano, M, Miyashige, Y, Eguchi, A, Ogata, Y, Goda, N, Iwai, K, Yamano, E, Watanabe, Y, Soga, T & Kataoka, Y 2015, 'Potential biomarkers of fatigue identified by plasma metabolome analysis in rats', PLoS One, vol. 10, no. 3, e0120106. https://doi.org/10.1371/journal.pone.0120106
Kume S, Yamato M, Tamura Y, Jin G, Nakano M, Miyashige Y et al. Potential biomarkers of fatigue identified by plasma metabolome analysis in rats. PLoS One. 2015 Mar 20;10(3). e0120106. https://doi.org/10.1371/journal.pone.0120106
Kume, Satoshi ; Yamato, Masanori ; Tamura, Yasuhisa ; Jin, Guanghua ; Nakano, Masayuki ; Miyashige, Yukiharu ; Eguchi, Asami ; Ogata, Yoshiyuki ; Goda, Nobuhito ; Iwai, Kazuhiro ; Yamano, Emi ; Watanabe, Yasuyoshi ; Soga, Tomoyoshi ; Kataoka, Yosky. / Potential biomarkers of fatigue identified by plasma metabolome analysis in rats. In: PLoS One. 2015 ; Vol. 10, No. 3.
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