Abstract
Recent studies have reported that plasma levels of tricarboxylic acid (TCA) cycle metabolites and TCA cycle-related metabolite change in patients with chronic fatigue syndrome (CFS) and in healthy humans after exercise. Exogenous dietary citric acid has been reported to alleviate fatigue during daily activities and after exercise. However, it is unknown whether dietary citric acid affects the plasma levels of these metabolites. Therefore, the present study aimed to investigate the effects of exogenously administered citric acid on TCA cycle metabolites and TCA cycle-related metabolites in plasma. Sprague-Dawley rats were divided into control and citric acid groups. We evaluated the effect of exogenous dietary citric acid on the plasma TCA cycle and TCA cycle-related metabolites by metabolome analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). TCA cycle metabolites, including plasma citrate, cis-aconitate, and isocitrate, were significantly elevated after exogenous administration of citric acid. Anaplerotic amino acids, which are converted to TCA cycle metabolites, such as serine, glycine, tryptophan, lysine, leucine, histidine, glutamine, arginine, isoleucine, methionine, valine, and phenylalanine, also showed significantly elevated levels. Citric acid administration significantly increased the levels of initial TCA cycle metabolites in the plasma. This increase after administration of citric acid was shown to be opposite to the metabolic changes observed in patients with CFS. These results contribute novel insight into the fatigue alleviation mechanism of citric acid.
Highlights
Dietary citric acid intake alleviates fatigue [1]
Isoleucine, valine, and methionine are anaplerotic substrates that are converted to succinyl-CoA, and their plasma levels were significantly higher in rats in the citric acid group than in control rats
We determined the effects of exogenous dietary citric acid intake on the tricarboxylic acid (TCA) cycle and TCA cycle-related metabolites in rat plasma, using LC-MS/MS analysis, thereby revealing the following effects of citric acid administration: 1) initial TCA cycle metabolites, namely citrate, cis-aconitate, and isocitrate, were significantly higher, whereas α-ketoglutarate tended to be high; 2) levels of anaplerotic amino acids, which are converted to TCA cycle metabolites, namely serine, glycine, tryptophan, lysine, leucine, histidine, glutamine, arginine, isoleucine, methionine, valine, and phenylalanine, increased significantly
Summary
Dietary citric acid intake alleviates fatigue [1]. Double-blind, placebo-controlled, parallel group studies reported that citric acid alleviates fatigue in daily activities [2, 3]. Intake of citric acid before exercise reportedly attenuates physical fatigue and the feeling of fatigue [4, 5, 6, 7]. Free citric acid has been reported to alleviate fatigue [1, 2, 3, 4, 5]. Dietary citric acid has a markedly low possibility of participating in the TCA cycle [15]
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