Research Progress on the Mechanisms of Natural Products with Anti-Exercise Fatigue Activity

With the deepening of modern Chinese medicine research, the active chemical components in Chinese medicinal herbs have gradually become clear. Studies have shown that astragalus, Korean ginseng, dendrobium officinale, and other herbs possess significant anti-exercise fatigue activities. Furthermore, various natural substances derived from food, such as wheat oligopeptides, corn germ peptides, and pleurotus eryngii polysaccharides, have also been proven to exhibit certain anti-exercise fatigue activities. According to the "Implementation Manual of Technical Specifications for Inspection and Evaluation of Health Food" issued by the National Medical Products Administration of China, the criteria for determining anti-fatigue health food are as follows: "Positive results in the weighted swimming test, combined with positive results in any two of the three indicators - blood lactate, serum urea nitrogen, and liver glycogen - can indicate that the tested sample has the function of alleviating physical fatigue." Currently, research on the anti-exercise fatigue activities of natural substances primarily employs animal experiments using rats, mice, and other species. These studies assess endurance through tests such as weighted swimming, pole climbing, and forelimb grip strength, combined with the analysis of physiological and biochemical indicators such as lactic acid in serum, blood urea nitrogen (BUN), and liver glycogen content.

Regarding the generation mechanisms of exercise-induced fatigue (Part I), the underlying mechanisms of natural substances' anti-exercise fatigue activity primarily encompass inhibiting the accumulation of neurotransmitters, enhancing the reserve of energy substances within the body, promoting fat as an energy source, maintaining redox homeostasis, reducing the accumulation of metabolites, and augmenting mitochondrial biogenesis and repairing mitochondrial damage.

1. Inhibition of Neurotransmitter Accumulation

Numerous studies have indicated that during exercise, a significant increase in the concentration of 5-HT (serotonin) in the central nervous system accelerates the onset and progression of exercise-induced fatigue. Acorus tatarinowii (Shi Chang Pu) has been found to possess notable anti-exercise fatigue activity. Research has revealed that dietary supplementation with Acorus tatarinowii can significantly downregulate the expression of tryptophan hydroxylase-2 (TPH2) and 5-HT receptor 1B (5-HT1B) at both the mRNA and protein levels. TPH2 serves as a rate-limiting enzyme in the synthesis pathway of 5-HT, while 5-HT1B inhibits the synthesis and release of 5-HT. Reducing intracellular TPH2 concentration and increasing intracellular 5-HT1B concentration can both inhibit the accumulation of 5-HT in the central nervous system during exercise, thereby enhancing exercise endurance time. Substances such as verbascoside derived from Pedicularis tricolor and caffeine can also reduce the concentration of 5-HT in the central nervous system by regulating the expression of TPH2 and 5-HT1B, thereby delaying exercise-induced fatigue.

2.Enhancing Energy Substance Reserves

Glycogen, primarily stored in the liver and muscle tissues, serves as the primary energy source for the body during physical activities. Increasing the glycogen concentration in the liver and muscle tissues can delay exercise-induced fatigue caused by the depletion of energy substances. Studies have shown that dietary supplementation with natural substances derived from various Chinese medicinal herbs or food sources, such as Astragalus membranaceus, Rhodiola rosea, Radix Moupinensis, and Niuchangzhi mushroom, can elevate the reserves of hepatic and muscle glycogen in the body, thereby improving exercise-induced fatigue.

Within muscle tissues, glucose derived from the bloodstream is actively transported into cells, where it undergoes multiple enzymatic reactions to ultimately synthesize glycogen molecules. Glucose transporter 1 (GLUT1) and glucose transporter 4 (GLUT4) are responsible for efficiently transporting glucose into cells. When muscle contraction consumes energy, GLUT4 facilitates the transfer of a large amount of blood glucose into muscle tissues. Enhancing GLUT4 expression can significantly elevate intracellular glucose concentrations, thereby promoting glycogen synthesis. 5'-AMP-activated protein kinase (AMPK) serves as a crucial regulatory factor in energy metabolism, which can upregulate GLUT4 expression and facilitate glucose transport. Studies have found that the water-soluble extract of Pteris multifida can significantly upregulate the expression of GLUT4 and AMPK, increase glycogen concentrations in the liver and muscles, and prolong the swimming exhaustion time of rats. Additionally, pleurotus eryngii polysaccharides can significantly increase the content of hepatic and muscle glycogen in the body, while Ganoderma atrum polysaccharides can notably extend the duration of weighted swimming in mice, accompanied by a marked increase in their hepatic and muscle glycogen levels.

3.Enhancing Fat Metabolism for Energy Supply

Certain natural active substances can delay exercise-induced fatigue by promoting fat breakdown for energy supply and reducing glycogen consumption. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) serves as a primary regulator of intracellular glucose and fatty acid metabolism. On one hand, it upregulates the expression of GLUT1 and GLUT4, facilitating glucose entry from the bloodstream into cells. On the other hand, PGC-1α downregulates the expression of phosphofructokinase (PFK), inhibiting glucose glycolysis, and upregulates pyruvate dehydrogenase kinase 4 (PDK4) expression, inhibiting the activity of pyruvate dehydrogenase (PDH), thereby suppressing glucose oxidation for energy production. Additionally, PGC-1α promotes fat breakdown for energy supply by upregulating the expression of fatty acid transport protein (FAT/CD36), carnitine palmitoyltransferase 1 (CPT-1), and medium-chain acyl-CoA dehydrogenase (MCAD), enhancing the entry and breakdown of long-chain fatty acids within mitochondria for energy supply. Studies have found that dietary supplementation with Cordyceps militaris can improve the efficiency of fatty acid oxidation for energy supply, reducing glycogen consumption. Moreover, consuming water-soluble extracts of Periplaneta americana at doses ranging from 2.70 mg/20g to 5.41 mg/20g can significantly upregulate PGC-1α expression in mouse hepatocytes and myocytes, increasing hepatic and muscle glycogen reserves and delaying exercise-induced fatigue.

4.Maintaining Redox Homeostasis

During prolonged and high-intensity exercise, the body often experiences oxidative stress. Nrf2 is a crucial transcription factor in the body's response to oxidative damage, expressed in most tissues. Under normal conditions, Nrf2 binds to Kelch-like ECH-associated protein 1 (Keap1) and ubiquitin ligase Cullin 3 in the cytoplasm and is continuously degraded. However, during oxidative stress, Nrf2 dissociates from Keap1, migrates into the nucleus, and binds to the antioxidant response element (ARE) promoters of relevant antioxidant genes within the nucleus, promoting their transcription and translation processes. This results in the production of antioxidant enzymes or proteins that eliminate excess free radicals, thereby maintaining redox homeostasis in the body. Nrf2 is activated during acute exercise to counteract the excess reactive oxygen species (ROS) generated during exercise. When Nrf2 is blocked, the sensitivity of the myocardium to oxidative stress increases, accelerating the depletion of the endogenous antioxidant GSH, leading to more severe oxidative damage to cells, tissues, and organs. Studies have found that after 4 weeks of dietary supplementation with Korean ginseng at doses ranging from 1g/d to 2g/d, subjects exhibited significant reductions in blood concentrations of ROS and malondialdehyde (MDA). Furthermore, dietary supplementation with Antrodia camphorata mycelium at doses of 0.3 g/kg and 0.9 g/kg significantly improved the swimming and running exhaustion times of mice. This mechanism is related to the increased concentrations of GSH-Px and superoxide dismutase (SOD) in muscle and liver cells, as well as the decreased concentrations of ROS in these cells.

5.Reducing Metabolite Accumulation

The concentrations of lactate in the blood and blood urea nitrogen (BUN) are commonly used indicators to evaluate the anti-exercise fatigue activity of natural substances. Lactate is produced through glycolysis during high-intensity exercise and serves as a marker of anaerobic glucose metabolism in the body. As exercise intensity increases, lactate accumulates in muscle tissues and the bloodstream. This accumulation of lactate lowers the pH value, reducing glycogenolysis efficiency and affecting the excitation-contraction coupling process in skeletal muscles, ultimately leading to exercise-induced fatigue. Elevated ammonia concentrations in the body can impair the function of the central nervous system, affecting energy metabolism and neurotransmitter transmission in the brain tissue, thereby contributing to exercise-induced fatigue. Research has shown that various natural substances possess the ability to lower blood lactate and BUN concentrations. A mixture of puffed grains and Cordyceps militaris can enhance the activity of total lactate dehydrogenase (LDH) in serum, significantly reducing blood lactate concentrations in mice.

6.Enhancing Mitochondrial Biogenesis and Repairing Mitochondrial Damage

The performance during both short-term and long-term physical activities is influenced by the lag time for the oxidative phosphorylation rate in mitochondria to reach a steady state. During the initial minutes of exercise and the gradual increase in exercise intensity, it takes time for the oxidative phosphorylation rate to stabilize. This process is affected by muscle energy levels, the availability of O2, and the activation of metabolism-related enzymes. One factor contributing to slow oxidative metabolism and limited exercise endurance is the insufficiency of acetyl groups caused by exercise. Carnitine acetyltransferase (CrAT), a mitochondrial enzyme, regulates the interconversion of acetyl-CoA and acetylcarnitine and the economical utilization of muscle energy. The buffering of acetyl groups within mitochondria mediated by CrAT is a crucial factor in optimizing exercise performance. Studies have found that specific knockout of the CrAT gene in mouse skeletal muscle significantly impairs exercise capacity compared to wild-type mice, regardless of exercise intensity, with increased glycogen consumption and reduced oxygen utilization efficiency. L-carnitine has been shown to enhance CrAT mRNA expression, and supplementation with L-carnitine before exercise effectively prolonged the treadmill exhaustion time in normal mice. However, in CrAT knockout mice, L-carnitine supplementation did not affect exercise endurance. Research indicates that natural substances such as astragalus polysaccharides and dendrobium officinale extracts from traditional Chinese medicine, as well as myricetin, anthocyanins, rutin, and lycopene from food sources, possess biological activities that enhance mitochondrial biogenesis and repair mitochondrial damage. Myricetin, for example, promotes mitochondrial biogenesis in skeletal muscle cells by upregulating PGC-1α, SIRT1, NRF-1, and AMPK, thereby contributing to anti-exercise fatigue effects.

References

[1] Ni Bingqian, Li Xiuting, Zhang Chengnan, et al. Research Progress on Molecular Mechanisms of Natural Substances Against Exercise-Induced Fatigue [J]. Food Research and Development, 2023, 44(10): 208-214.

[2] Chen Hui, Ma Xuan, Cao Lixing, et al. Research Progress on the Mechanisms of Exercise Fatigue and Food-Derived Anti-Fatigue Active Components [J]. Food Science, 2020, 41(11): 247-258.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.