title: Potential biomarkers of fatigue identified by plasma metabolome analysis in rats.
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.
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors: Satoshi
authors: S
authors: Kume
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors: Masanori
authors: M
authors: Yamato
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors: Yasuhisa
authors: Y
authors: Tamura
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors: Guanghua
authors: G
authors: Jin
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan; Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Masayuki
authors: M
authors: Nakano
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors: Yukiharu
authors: Y
authors: Miyashige
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors: Asami
authors: A
authors: Eguchi
authors: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors: Yoshiyuki
authors: Y
authors: Ogata
authors: Department of Life Science and Medical Bio-Science, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors: Nobuhito
authors: N
authors: Goda
authors: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kazuhiro
authors: K
authors: Iwai
authors: Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Emi
authors: E
authors: Yamano
authors: Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan; Pathophysiological and Health Science Team, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan.
authors: Yasuyoshi
authors: Y
authors: Watanabe
authors: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
authors: Tomoyoshi
authors: T
authors: Soga
authors: Cellular Function Imaging Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe, Hyogo, Japan; Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Yosky
authors: Y
authors: Kataoka
mesh_terms: D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D019075:Electrophoresis, Capillary; D005221:Fatigue / Q000097:blood*; D008297:Male; D055442:Metabolome / Q000502:physiology*; D009569:Nitric Oxide / Q000097:blood; D051381:Rats
chemical_list: D015415:Biomarkers; D009569:Nitric Oxide; D000255:Adenosine Triphosphate