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Hesperidin Functions as an Ergogenic Aid by Increasing Endothelial Function and Decreasing Exercise-Induced Oxidative Stress and Inflammation, Thereby Contributing to Improved Exercise Performance

M. Imperatrice, I. Cuijpers, F.J. Troost, M.M.J.P.E. Sthijns.
Exercise Performance. Nutrients (2022), 14, 2955.
https://doi.org/10.3390/nu14142955

Abstract
The regulation of blood flow to peripheral muscles is crucial for proper skeletal muscle functioning and exercise performance. During exercise, increased mitochondrial oxidative phosphorylation leads to increased electron leakage and consequently induces an increase in ROS formation, contributing to DNA, lipid, and protein damage. Moreover, exercise may increase blood- and intramuscular inflammatory factors leading to a deterioration in endurance performance. The aim of this review is to investigate the potential mechanisms through which the polyphenol hesperidin could lead to enhanced exercise performance, namely improved endothelial function, reduced exercise-induced oxidative stress, and inflammation. We selected in vivo RCTs, animal studies, and in vitro studies in which hesperidin, its aglycone form hesperetin, hesperetin-metabolites, or orange juice are supplemented at any dosage and where the parameters related to endothelial function, oxidative stress, and/or inflammation have been measured. The results collected in this review show that hesperidin improves endothelial function (via increased NO availability), inhibits ROS production, decreases production and plasma levels of pro-inflammatory markers, and improves anaerobic exercise outcomes (e.g., power, speed, energy). For elite and recreational athletes, hesperidin could be used as an ergogenic aid to enhance muscle recovery between training sessions, optimize oxygen and nutrient supplies to the muscles, and improve anaerobic performance.

 

 (A) Exhaustive exercise leads to macrophage activation, which activates an acute inflammatory response characterized by increases in circulatory and intramuscular inflammatory markers such as C-reactive protein (CRP), cytokines (tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β). Without adequate post-exercise/competition recovery periods, an excessive inflammatory response could lead to impaired muscle contractions and force generation. (B) Hesperidin shows the potential to inhibit macrophage activation and recruitment and decrease markers of exercise-induced inflammation, potentially speeding up the recovery process and, therefore, improving exercise performance. The figure was created with BioRender.com. Abbreviations: CRP = C-reactive protein; HES = hesperidin; IL-1β = interleukin-1beta; IL-6 = interleukin-6; TNF-α = tumour necrosis factor-alpha; Increased: ↑ < ↑↑; Decreased: ↓ < ↓↓
 

(A) Contractile activity of skeletal muscle tissue leading to a higher oxygen demand could induce an increased formation of ROS as a result of the excessive mitochondrial activity leading to incomplete oxidative phosphorylation during exercise. In athletes performing extreme endurance exercise, the constant rise in ROS production could lead to damage to DNA, lipids (lipid peroxidation), or protein and attenuation in muscle contraction. (B) Increased blood flow (and thereby increased shear stress) during exercise leads to increased endothelial ROS production, which reacts with NO. Increased ROS production by the endothelium leads to decreased NO availability. (C) Hesperidin, acting as an antioxidant, helps to prevent the side effects of excessive ROS formation in the muscle cells. Moreover, hesperidin increases endogenous antioxidant enzymes. These two mechanisms combined help prevent cell damage and the decline in muscle contraction signalling pathways leading to stimulation in force production. (D) When supplemented with hesperidin, endothelial ROS production will be decreased, preventing the decrease in NO production caused by shear stress. The figure was created with BioRender.com. Abbreviations: HES = hesperidin; NO = nitric oxide; NOX = NADPH oxidase; O2 = oxygen; ROS = reactive oxygen species; Increased: ↑ < ↑↑; Decreased: ↓ < ↓↓

Schematic summary of the potential mechanism of action for the hesperidin effect on endothelial function during exercise. (A) During exercise, the release of nitric oxide (NO) by endothelial cells causes the relaxation of the smooth muscle cells, which leads to the dilation of an artery and an increase in blood flow. (B) Hesperidin increases the endothelial cells’ NO production. This process leads to higher artery dilation, which further improves blood flow. During exercise, improved skeletal muscle perfusion and the consequent increase in oxygen (O2) efflux to the muscle can improve endurance performance. The figure was created with BioRender.com. Abbreviations: HES = hesperidin; NO = nitric oxide; O2 = oxygen; SKM = skeletal muscle; Increased: ↑ < ↑↑; Decreased: ↓ < ↓↓