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Tyrosine as a Mechanistic-Based Biomarker for Brain Glycogen Decrease and Supercompensation With Endurance Exercise in Rats: A Metabolomics Study of Plasma.

ABSTRACT: Brain glycogen, localized in astrocytes, produces lactate as an energy source and/or a signal factor to serve neuronal functions involved in memory formation and exercise endurance. In rodents, 4 weeks of chronic moderate exercise-enhancing endurance and cognition increases brain glycogen in the hippocampus and cortex, which is an adaption of brain metabolism achieved through exercise. Although this brain adaptation is likely induced due to the accumulation of acute endurance exercise-induced brain glycogen supercompensation, its molecular mechanisms and biomarkers are unidentified. Since noradrenaline synthesized from blood-borne tyrosine activates not only glycogenolysis but also glycogenesis in astrocytes, we hypothesized that blood tyrosine is a mechanistic-based biomarker of acute exercise-induced brain glycogen supercompensation. To test this hypothesis, we used a rat model of endurance exercise, a microwave irradiation for accurate detection of glycogen in the brain (the cortex, hippocampus, and hypothalamus), and capillary electrophoresis mass spectrometry-based metabolomics to observe the comprehensive metabolic profile of the blood. Endurance exercise induced fatigue factors such as a decrease in blood glucose, an increase in blood lactate, and the depletion of muscle glycogen, but those parameters recovered to basal levels within 6 h after exercise. Brain glycogen decreased during endurance exercise and showed supercompensation within 6 h after exercise. Metabolomics detected 186 metabolites in the plasma, and 110 metabolites changed significantly during and following exhaustive exercise. Brain glycogen levels correlated negatively with plasma glycogenic amino acids (serine, proline, threonine, glutamate, methionine, tyrosine, and tryptophan) (r < -0.9). This is the first study to produce a broad picture of plasma metabolite changes due to endurance exercise-induced brain glycogen supercompensation. Our findings suggest that plasma glycogenic amino acids are sensitive indicators of brain glycogen levels in endurance exercise. In particular, plasma tyrosine as a precursor of brain noradrenaline might be a valuable mechanistic-based biomarker to predict brain glycogen dynamics in endurance exercise.

SUBMITTER: Matsui T

PROVIDER: S-EPMC6433992 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: The AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that becomes activated by exercise and binds glycogen, an important energy store required to meet exercise-induced energy demands. Disruption of AMPK-glycogen interactions in mice reduces exercise capacity and impairs whole-body metabolism. However, the mechanisms underlying these phenotypic effects at rest and following exercise are unknown. Furthermore, the plasma metabolite responses to an acute exercise challenge in mice remain largely uncharacterized. Methods: Plasma samples were collected from wild type (WT) and AMPK double knock-in (DKI) mice with disrupted AMPK-glycogen binding at rest and following 30-min submaximal treadmill running. An untargeted metabolomics approach was utilized to determine the breadth of plasma metabolite changes occurring in response to acute exercise and the effects of disrupting AMPK-glycogen binding. Results: Relative to WT mice, DKI mice had reduced maximal running speed (p < 0.0001) concomitant with increased body mass (p < 0.01) and adiposity (p < 0.001). A total of 83 plasma metabolites were identified/annotated, with 17 metabolites significantly different (p < 0.05; FDR<0.1) in exercised (↑6; ↓11) versus rested mice, including amino acids, acylcarnitines and steroid hormones. Pantothenic acid was reduced in DKI mice versus WT. Distinct plasma metabolite profiles were observed between the rest and exercise conditions and between WT and DKI mice at rest, while metabolite profiles of both genotypes converged following exercise. These differences in metabolite profiles were primarily explained by exercise-associated increases in acylcarnitines and steroid hormones as well as decreases in amino acids and derivatives following exercise. DKI plasma showed greater decreases in amino acids following exercise versus WT. Conclusion: This is the first study to map mouse plasma metabolomic changes following a bout of acute exercise in WT mice and the effects of disrupting AMPK-glycogen interactions in DKI mice. Untargeted metabolomics revealed alterations in metabolite profiles between rested and exercised mice in both genotypes, and between genotypes at rest. This study has uncovered known and previously unreported plasma metabolite responses to acute exercise in WT mice, as well as greater decreases in amino acids following exercise in DKI plasma. Reduced pantothenic acid levels may contribute to differences in fuel utilization in DKI mice.

Project description:Available evidence indicates that ketone bodies inhibit glycolysis in contracting muscles. Therefore, we investigated whether acute exogenous ketosis by oral ketone ester (KE) intake early in a simulated cycling race can induce transient glycogen sparing by glycolytic inhibition, thereby increasing glycogen availability in the final phase of the event. In a randomized crossover design, 12 highly trained male cyclists completed a simulated cycling race (RACE), which consisted of 3-h intermittent cycling (IMT180'), a 15-min time trial (TT15'), and a maximal sprint (SPRINT). During RACE, subjects received 60 g carbohydrates/h combined with three boluses (25, 20, and 20 g) (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) or a control drink (CON) at 60 and 20 min before and at 30 min during RACE. KE intake transiently increased blood d-?-hydroxybutyrate to ~3 mM (range: 2.6-5.2 mM) during the first half of RACE (P < 0.001 vs. CON). Blood pH concomitantly decreased from approximately 7.42 to 7.36 (range: 7.29-7.40), whereas bicarbonate dropped from 26.0 to 21.6 mM (range: 20.1-23.7; both P < 0.001 vs. CON). Net muscle glycogen breakdown during IMT180' [KE: -78?±?30 (SD); CON: -60?±?22 mmol/kg wet wt; P = 0.08] and TT15' (KE: -9?±?18; CON: -18?±?18 mmol/kg wet wt; P = 0.35) was similar between KE and CON. Accordingly, mean power output during TT15' (KE: 273?±?38; CON: 272?±?37 W; P = 0.83) and time-to-exhaustion in the SPRINT (KE: 59?±?16; CON: 58?±?17 s; P = 0.66) were similar between conditions. In conclusion, KE intake during a simulated cycling race does not cause glycogen sparing, nor does it affect all-out performance in the final stage of a simulated race.NEW & NOTEWORTHY Exogenous ketosis produced by oral ketone ester ingestion during the early phase of prolonged endurance exercise and against the background of adequate carbohydrate intake neither causes muscle glycogen sparing nor improves performance in the final stage of the event. However, such exogenous ketosis may decrease buffering capacity in the approach of the final episode of the event. Furthermore, ketone ester intake during exercise may reduce appetite immediately after exercise.

Project description:The goal of the endurance exercise training study in young adult rats was to perform exercise training studies in young adult (6-month-old) F344 rats, and from these rats collect multiple tissues in order to provide high quality samples for detailed analysis by chemical analysis sites. Tissues were collected from 10-12 rats sedentary control rats concurrent with the collection of the 8-week training groups. The 8-week training group and controls were from the same cohort and same age at euthanasia. For the older age group, an additional set of controls (n=5-6) were collected with the 1-2 week training group. Rats were either sedentary or underwent an exercise training program. Rats were exercised on the rodent treadmill 5 days per week using a progressive training protocol designed to exercise the rats at approximately 70% of VO2max and training was performed no earlier than 10:00 am and no later than 5:00 pm over 5 consecutive days per week. Training was initiated with the treadmill set at 70% of VO2 max and 5 degrees grade for 20 minutes. The duration of exercise was increased by one minute each day until day 31 of training (start of week 7), when a duration of 50 min was reached. Speed and grade of each training session increased in larger increments due to treadmill parameters. The highest intensity and duration of training began on day 31. This intensity was maintained for the final 10 days of the protocol to ensure steady state had been achieved. If any rats were unable to perform at least 4 days of training per week they were removed from the study and euthanized. It is important to note that the starting treadmill speed varied depending on the sex and age of the rat. The initial and maximum speeds were based on VO2max measurements obtained during the pre-training testing of the compliant rats. Rats assigned to the control group followed a schedule similar to the training group. They were placed in one lane on the treadmill for 15 minutes/day, 5 days per week. The treadmill was set at 0 m/min at an incline that corresponded to the incline being used by the training group.

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Tyrosine as a Mechanistic-Based Biomarker for Brain Glycogen Decrease and Supercompensation With Endurance Exercise in Rats: A Metabolomics Study of Plasma.

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