Plasma samples were collected from subjects in the training set between 9:00 a.m. and 12:00 p.m. All samples were collected from April 2012 to December 2012. Before Int J Sports Med 16, 155159, doi: 10.1055/s-2007-972984 (1995). The subjects in this study were 133 Japanese adults, namely, 67 CFS patients and 66 healthy controls. & Huang, P. L. Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice. Okada, T., Tanaka, M., Kuratsune, H., Watanabe, Y. In a similar manner, the pyruvate/isocitrate ratio was also used as another index to assess the activity of glycolysis and the TCA cycle. All testing sessions included exercising on a cycle ergometer at 50%-60% of their max power output for 30 min followed by performing the Thorstensson test on an isokinetic dynamometer. Citrulline malate is composed generally in the ratio of 2:1 of citrulline, a nonessential amino acid, and malate, a Krebs cycle Prez-Guisado, J and Jakeman, PM. This approach enabled comprehensive analysis of the metabolic profile in various pathways with high reproducibility. How to cite this article: Yamano, E. et al. This suggested that activation of the fatigue metabolic pathway contributes to the supply of energy that has been reduced under the fatigued condition. Dietary Arginine and Citrulline Supplements for Cardiovascular Health and Athletic Performance: A Narrative Review. In summary, our study has demonstrated a profile of abnormal energy metabolism resulting from deficiencies in aconitase activity in the TCA cycle and dysregulation in the urea cycle in CFS patients. However, many individuals with these disorders have orthostatic intolerance and rapid heart rates and these are worsened. This study was supported by the Core Research for Evolutional Science and Technology (CREST) Program of the Japan Science and Technology Agency (JST), a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government to Y. K. (JSPS KAKENHI Grant Number 25460399, 15H00905), Japan Agency for Medical Research and Development to Y. K., Cross-ministerial Strategic Innovation Promotion Program (SIP) to Y. K., RIKEN Rijicho Fund and research grants from Yamagata Prefecture and Tsuruoka City. J Biol Chem 281, 1676816776, doi: 10.1074/jbc.M601876200 (2006). Soga, T. et al. These analyses were conducted using JMP (ver. Unauthorized use of these marks is strictly prohibited. Diagnosis and treatment of ME/CFS requires a coordinated team effort on the part of the patient, physician, ancillary staff and oftentimes a dietician and exercise physiologist. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Citrulline malate (CM) ingestion significantly reduced fatigue sensation, improved aerobic energy production in muscles, and improved exercise tolerance ( Sureda and Pons, 2012 ), thus greatly enhancing aerobic performance and prolongation of onset of muscular fatigue ( Kaore et al., 2013). Table 1 summarizes the demographic and clinical characteristics of the CFS patients and healthy controls used in this study. Keywords: Citrulline is an important amino acid for the urea cycle, which helps your body to get rid of harmful substances like ammonia. 102cm; Nacalai Tesque, Kyoto, Japan), chemically coated with cationic polymer, was used as the separation capillary. Jong, C. J., Azuma, J. Tanaka, M. et al. Google Scholar. (3) These procedures were repeated up to 10 times, and the accuracy of the model was evaluated using the predictions of validation data. Our findings can be attributed to a distinctive metabolic pathway in the fatigued condition: the metabolic flow from ornithine and glutamine to succinate of the TCA cycle via gamma-aminobutyric acid (GABA)36,37. L-citrulline is a nonessential amino acid involved in the urea cycle that acts as an endogenous precursor of L-arginine, being a more efficient alternative to L-arginine to increase the plasma concentration of L-arginine through the nitric oxide synthase (NOS) pathway. PubMed Central Cite this article. Exact mass data were acquired at a rate of 1.5 spectra/s over the m/z range of 501,000. Ornithine and citrulline, which is produced from ornithine and carbamyl phosphate by ornithine transcarbamylase, are involved in the major function of detoxification in the liver40. B. Jr. Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Ann Intern Med 121, 953959 (1994). There is a wide range of differential diagnostic possibilities in individuals who have a chronic-fatigue-type presentation. Consequently, the ratio of pyruvate/isocitrate was significantly higher in CFS patients than in healthy controls (P<0.01), reflecting a disturbance in the link between glycolysis and the TCA cycle. Kataoka, Y. et al. PubMed Central The discrimination ability of the model was assessed by ROC analysis and its AUC value. Hung, Gigin Lin, Chih-Yung Chiu, Carolina Gonzalez-Riano, Jorge Saiz, Pilar Amiano, M. Marcinkiewicz-Siemion, M. Kaminski, K. A. Kaminski, Stephan Klatt, James D. Doecke, Blaine R. Roberts, Adoracion Pegalajar-Jurado, Bryna L. Fitzgerald, Claudia R. Molins, Lina A. Dahabiyeh, Refat M. Nimer, Anas Abdel Rahman, Scientific Reports Drapier, J. C. & Hibbs, J. We constructed a swimming exercise protocol, in which mice were subjected to exhaustive swimming with a load of 5% body weight, and measured the time until exhaustion, the blood levels of lactate and ammonia, and the glycogen content of the gastrocnemius and biceps femoris muscles. Hi everyone, I suffer from chronic fatigue syndrome, and have been advised to try (besides the tons of things I tried without success) citrulline malate. Your email address will not be published. and transmitted securely. Sample solution (30nl) was injected at 50mbar for 30s, and a voltage of 30kV was applied. Epub 2021 Aug 21. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. In addition to the previous study33, the findings that CFS patients who were recruited from the same hospital as the present study showed higher oxidative stress relative to healthy controls34 supports the hypothesis that the predominant reduction of isocitrate may result from the inactivation of aconitase via chronic oxidative stress. What happens is there is oxidative damage to DNA molecules, and this can cause damage to subcellular particles such as mitochondria. (a) The training data were used for development and internal validation of the model, starting from support vector machine-feature selection, feature selection based on metabolic pathways, model development and internal validation. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/, Yamano, E., Sugimoto, M., Hirayama, A. et al. Standard mixtures including these internal standards were also measured and metabolite concentrations of each sample were calculated based on the ratio of these relative peak areas. We firstly selected metabolites which showed large margin between CFS and healthy controls, e.g. Bookshelf 2021 Dec;121(12):3283-3295. doi: 10.1007/s00421-021-04774-6. In addition, the levels of BCAAs and tyrosine, cysteine, methionine, lysine and arginine were decreased in cases with mental fatigue16. Gough LA, Sparks SA, McNaughton LR, Higgins MF, Newbury JW, Trexler E, Faghy MA, Bridge CA. These have also shown impaired oxidative phosphorylation and damage to the mitochondria. Drinking rapidly a small bottle of plain water on awakening before even getting up out of bed activated the sympathetic nervous system and is useful to start the day as mornings are usually very tough times on patients. Cell Biochem Funct. Citrullline malate (CM) is a commonly sold over the counter ergogenic aid that has been gaining popularity due to its proposed ability to aid in reducing fatigue by increasing blood flow (1). As for the BCAAs, they did not show any significant difference in CFS relative to healthy controls. Copyright 2017-22 by Dr. Nicholas DePace | Website Designed & Developed by. Considering this, CFS might not involve sustained muscle stress. Circulation 103, 30993104 (2001). Muscle or joint pain. *P<0.05; ***P<0.001; ****P<0.0001 (MannWhitney U-test). Blomstrand, E., Hassmen, P., Ekblom, B. 2023 Apr 6. doi: 10.1519/JSC.0000000000004095. FOIA Accessibility This site needs JavaScript to work properly. Nutrition 24, 599603, doi: 10.1016/j.nut.2008.03.001 (2008). As a rigorous validation, 200 trials of 10-fold cross validation (CV) yielded a high median value of AUC values: 0.784 (95% CI: 0.7830.785), and 200 resampling trials also yielded high AUC values: 0.790 (95% CI: 0.7830.796) and 0.758 (95% CI: 0.7410.768) for the training and validation datasets, respectively. Amino Acids 42, 22232232, doi: 10.1007/s00726-011-0962-7 (2012). Kume, S. et al. (b) Box-and-whisker plots of the probability of chronic fatigue syndrome yielded by the developed model. Automatic recalibration of each acquired spectrum was performed using the masses of reference standards ([13C isotopic ion of deprotonated acetic acid dimer (2CH3COOH-H)], m/z 120.038339), and ([hexakis + deprotonated acetic acid (CH3COOH-H)], m/z 680.035541). Another study reported that thiobarbituric acid-reactive lipoperoxide was increased in the liver tissue of fatigued animals44. The HPA axis and the genesis of chronic fatigue syndrome. The combination of ornithine/citrulline and pyruvate/isocitrate ratios discriminated CFS patients from healthy controls, yielding area under the receiver operating characteristic curve values of 0.801 (95% confidential interval [CI]: 0.7110.890, P<0.0001) and 0.750 (95% CI: 0.5840.916, P=0.0069) for training (n=93) and validation (n=40) datasets, respectively. Nat Rev Microbiol 3, 557565, doi: 10.1038/nrmicro1177 (2005). Google Scholar. Citrulline Malate Dosage & Side Effects. Therefore, the comprehensive analysis of metabolites has been used to characterize the pathophysiology of various disease states and thus to assist in drug discovery, disease diagnostics and treatments17,18. The first experimental testing session for each dosing period was considered the baseline day, the second session the acute day, and the third session the chronic day, which followed seven consecutive days of supplementation. FEBS Lett 443, 285289 (1999). The classical prototype patient is one who has a sudden onset of symptoms after being highly functioning. Despite these discrepancies, the previous study indicated that dysfunctional energy metabolism through the citric acid cycle is a fatigue phenotype21. Fletcher, M. A. et al. In fatigued animals, a previous study showed that plasma NOX levels were increased, and plasma oxidative levels were also elevated19. Ammonium acetate (5mM) in 50% methanolwater (v/v) containing 0.1M hexakis was delivered as the sheath liquid at 10l/min. J Clin Invest 78, 790797, doi: 10.1172/JCI112642 (1986). The use of traditional Chinese medicines in relieving exercise-induced fatigue. Serum amino acid concentrations in nine athletes before and after the 1993 Colmar ultra triathlon. Citrulline supplementation significantly increased the swimming time until exhaustion. It is believed that many patients have a genetic predisposition to this. Plos One 10, e0120106, doi: 10.1371/journal.pone.0120106 (2015). Here, we performed comprehensive metabolomic analyses of 133 plasma samples obtained from CFS patients and healthy controls to establish an objective diagnosis of CFS. 2016 Sep 16;13(10):730-740. doi: 10.7150/ijms.16132. The versatility of the model was validated using 200 trials of 10-fold CV as follows. People take L-citrulline supplements to improve blood flow, which may: 1. Increased ornithine in the urea cycle in the fatigued condition may cause upregulation of the flow of glutamate into the TCA cycle via GABA and the succinate pathway. blood flow; ergogenic aid; force; power; sports performance. Federal government websites often end in .gov or .mil. The pathogenesis of CFS remains incompletely understood and is thought to be multifactorial, including abnormalities of the central nervous system3,4,5, immune system6 and the hypothalamopituitaryadrenal axis7. There is also an increase in omega-6 PUFA and saturated fats in individuals with ME/CFS. It is a challenge to physicians both to diagnosis and treat. 3. With AUC values of 0.801 (95% CI: 0.7110.890, P<0.0001) and 0.750 (95% CI: 0.5840.916, P=0.0069) for the training and validation datasets, respectively, the two ratios of pyruvate/isocitrate and ornithine/citrulline levels in plasma could be used to distinguish between CFS patients and healthy controls. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. Chronic fatigue syndrome and mitochondrial dysfunction. Missing values were replaced by half of the minimal value of each metabolite for each set of data (as described elsewhere50 with slight modification). Omega-3 supplementation, which is anti-inflammatory, is also helpful as is a Mediterranean diet, which incorporates fish and other omega-3 products. Armstrong, C. W. et al. Oxidative damage is also a risk factor for atherosclerosis and neurodegeneration and therefore this may explain increased cardiovascular morbidity and mortality, which can potentially occur with chronic fatigue syndrome, as all of these processes involve oxidative damage to DNA. Save my name, email, and website in this browser for the next time I comment. https://doi.org/10.1038/srep34990. Chronic fatigue syndrome (CFS) is also called myalgic encephalomyelitis (ME). The Effect of Citrulline Malate Supplementation on Muscle Fatigue Among Healthy Participants. For metabolite analysis, samples were dissolved in 50l of Milli-Q water containing 200M each of 3-aminopyrrolidine and trimesic acid for CE-TOFMS. In the present study, the concentrations of citrate and isocitrate in the first steps of the TCA cycle related to the energy metabolism in CFS patients were reduced relative to those in healthy controls. The cause of ME/CFS is unknown. The increase of alpha-melanocyte-stimulating hormone in the plasma of chronic fatigue syndrome patients. Plos One 5, e10817, doi: 10.1371/journal.pone.0010817 (2010). Google Scholar. Other previous studies have reported the amino acid disturbances in CFS using nuclear magnetic resonance (NMR) spectroscopy, which is useful for simplified screening with a limited number of detected metabolites20,21. J-STAGE, Japan Science and Technology Information Aggregator, Electronic. Article Previous studies demonstrate that a daily dose of 6-8g of citrulline malate is sufficient to induce an ergogenic effect, though doses as low as 3g still offer performance benefits. Also, there are higher TNF alpha levels, IL-1 and IL-6 levels and increased IgA response against lipoproteins of commensal bacteria, the so called gut leak phenomena. Elastaselevels are also noted to be elevated in patients with CFS compared to healthy controls. Additional studies with a larger patient population should be performed to confirm the metabolic dysregulation in the TCA cycle and the urea cycle, which are thought to reflect the pathophysiological state in CFS. Metabolic footprinting and systems biology: the medium is the message. Our results also showed that the ornithine/citrulline ratio was significantly higher in CFS patients than in healthy controls. It is actually an independent unique disease. Summar, M. L. Molecular genetic research into carbamoyl-phosphate synthase I: molecular defects and linkage markers. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Effects of citrulline supplementation on exercise performance in humans: A review of the current literature. The peaks without assignment, but which showed potential discriminating ability, should also be analysed in future studies to identify other markers and provide a more accurate discrimination. Soga, T. et al. Shishioh-Ikejima, N. et al. J Biol Chem 256, 41274132 (1981). Citrulline Malate: "Citrulline malate is a promising supplement that could boost nitric oxide and aerobic energy production, thereby increasing endurance across a session, power endurance during a single climb, and decreasing the pump the results from inadequate blood flow and increasing muscular acidity." Citrulline, also commonly referred to as L-citrulline, is a non-essential amino acid. 5.04; GraphPad Software Inc., San Diego, CA). M.S., S.K., G.J. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. CFS patients experience neuropsychological symptoms, including cognitive impairment, chronic widespread pain and depressive symptoms2. CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid (TCA) and urea cycles. We previously validated the utility of plasma metabolomic analysis in a rat model of relatively long-lasting fatigue using capillary electrophoresis mass spectrometry (CE-MS), and found a decrease in energy metabolism with a change in urea cycle metabolism, as well as changes in the levels of amino acids including BCAAs19. S.F., K.Y. Kim YH, Jung JI, Jeon YE, Kim SM, Oh TK, Lee J, Moon JM, Kim TY, Kim EJ. 100cm total length) filled with 1M formic acid as the electrolyte. It may be that the decrease in ATP production causes chronic fatigue symptoms, post-exertional malaise, impaired glucose utilization and glucose hypometabolism and cerebral hypoperfusion, the latter of which is extremely important in orthostatic intolerance syndromes. MathSciNet Glutamine as an Anti-Fatigue Amino Acid in Sports Nutrition. Its many health benefits include being anti-inflammatory, alleviating depression, and increasing your ability to tolerate exercise. Nitric oxide mediates Kupffer cell-induced reduction of mitochondrial energization in hepatoma cells: a comparison with oxidative burst. Google Scholar. A commercially available COSMO (+) capillary (50mm i.d. It's considered non-essential because your body makes it on its own, specifically in the liver and. (1) Virtual datasets were yielded by selecting individuals, allowing redundant selection (resampling). We thank Y. Nakatomi, M. Kagura, Y. Nonoguchi, T. Hakariya and K. Tanaka for their assistance in collecting the samples and data from the subjects. The decreased concentrations of metabolites in the first steps of the TCA cycle in CFS patients likely reflect the pathophysiology of fatigue, which shows the functional dysregulation of flow from pyruvate to isocitrate. The metabolites in glutamine metabolism and the BCAAs did not show significant differences between the CFS patients and the healthy controls. 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