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.

Keywords: brain glycogen; endurance exercise; metabolomics; plasma biomarker; supercompensation.

FIGURE 1

Endurance exercise induces a decrease and supercompensation in brain glycogen. (A) Blood lactate levels. (B) Blood glucose levels. (C) Glycogen levels in the plantaris muscle, cortex, hippocampus, and hypothalamus. Data are expressed as mean ± standard error (n = 5/group). ^∗P < 0.05; ^∗∗P < 0.01 vs. pre-exercise group.

FIGURE 2

Changes in the plasma metabolic profile with endurance exercise. (A) Principal component analysis (PCA) of metabolomics. (B) Hierarchical cluster analysis (HCA) of metabolomics. A total of 186 metabolites were measured, revealing that 44 metabolites were changed significantly with endurance exercise. PCA and HCA clearly indicated the difference of metabolic profiles between pre-exercise, post-0 h, and post-6 h.

FIGURE 3

A scatter plot of the fold change of the overlapping metabolites. This figure showed that 23 metabolites, including glycogenic amino acids (such as aspartate, tyrosine, and tryptophan) increased immediately after exercise (post-0 h) and decreased 6 h after exercise (post-6 h) (lower-right quadrant). Also, a metabolite, acetoacetate, decreased immediately after exercise (post-0 h) and increased 6 h after exercise (post-6 h) (upper-left quadrant).

FIGURE 4

Plasma glycogenic amino acids are associated with cortical glycogen levels during and following endurance exercise. Lines in scatter plots show significant correlation (P < 0.05) (Pearson’s product-moment correlations test).

FIGURE 5

Plasma glycogenic amino acids are associated with hippocampal glycogen levels during and following endurance exercise. Lines in scatter plots show significant correlation (P < 0.05) (Pearson’s product-moment correlations test).

FIGURE 6

Plasma glycogenic amino acids are associated with hypothalamic glycogen levels during and following endurance exercise. Lines in scatter plots show significant correlation (P < 0.05) (Pearson’s product-moment correlations test).

FIGURE 7

Hypothetical schema for tyrosine as a possible mechanistic-based biomarker predicting brain glycogen dynamics (A) during and (B) following endurance exercise. In the skeletal muscle, protein catabolism is activated to produce glycogenic amino acids including tyrosine. Tyrosine is released to the blood stream, and its level is increased. Blood tyrosine is taken up by the brain and is converted into noradrenaline in noradrenergic neurons. Noradrenaline activates cyclic adenosine monophosphate (cAMP) production via the β2-adrenaline receptor to activate glycogenolysis in a matter of minutes but takes hours to induce glycogenesis and supercompensation through expression of protein targeting to glycogen (PTG). This late onset of glycogen synthesis likely contributes to supercompensation following endurance exercise.