Exercise fatigue is a series of events occurring at multiple organ, cellular, and molecular levels, with an intricate underlying mechanism. Based on the pathways, sites, and modes of action of various physiological triggers, exercise fatigue can be classified into peripheral fatigue and central fatigue. Peripheral fatigue is typically defined as the impairment of muscle function, whereas central fatigue refers to the inability of the brain to sustain the drive necessary to generate the required force or output the necessary energy, encompassing processes within motor neurons and the central nervous system.

Although the exact mechanisms of central fatigue are not fully understood, studies have suggested that it may be related to the depletion or accumulation of certain neurotransmitters. 5-Hydroxytryptamine (5-HT), also known as serotonin, plays a crucial physiological role as a neurotransmitter in the central nervous system. It is synthesized from tryptophan as a precursor under the catalytic action of enzymes such as tryptophan hydroxylase (TPH). Research has indicated that changes in the concentration of 5-HT in neurons are closely related to central fatigue, and the accumulation of 5-HT in brain tissue can contribute to central fatigue.

Current research findings suggest that the accumulation of 5-HT in neuronal cells is primarily regulated by amino acid transporters in the blood-brain barrier. The precursor of 5-HT, tryptophan, and branched-chain amino acids (BCAA) competitively enter neurons from the blood through amino acid transporters in the blood-brain barrier. During prolonged, high-intensity exercise, BCAA in the blood are significantly consumed, allowing more tryptophan to enter neurons, resulting in increased production and excessive accumulation of 5-HT, ultimately leading to central fatigue.

Dopamine (DA) is the most abundant catecholamine neurotransmitter in the central nervous system. Studies have shown that DA can inhibit the activity of tryptophan hydroxylase (TPH), a rate-limiting enzyme in the 5-HT synthesis pathway, thereby inhibiting the formation of 5-HT. Research has found that a lower ratio of 5-HT/DA in the central nervous system can enhance athletic performance, while a higher ratio can decrease arousal, coordination, and motivation during exercise, leading to central fatigue.

Furthermore, according to Pavlovian theory, protective inhibition generated by the brain contributes to the onset of exercise fatigue. During intense mental or physical exercise, a large number of impulses stimulate corresponding neurons in the cerebral cortex, causing prolonged excitation. To prevent excessive consumption of energy substances such as glycogen, the cerebral cortex initiates protective inhibition when a certain threshold is reached, generating a sense of fatigue to signal the body to stop exercising. During prolonged and intense exercise, the plasma concentration of branched-chain amino acids (BCAA) decreases, leading to an increase in the ratio of aromatic amino acids (AAA) to BCAA. Additionally, the increased content of γ-aminobutyric acid (GABA) in the brain during fatigue also contributes to the inhibition of the cerebral cortex.

Energy depletion, metabolite accumulation, oxidative stress, and Ca2+ metabolism disorders are currently the mainstream theories regarding the mechanisms of fatigue generation. Their impacts on muscles and the central nervous system may directly lead to the onset of fatigue.

1. Energy Depletion

Adenosine triphosphate (ATP) serves as the direct energy source for various life activities in the human body, while nutrients such as carbohydrates, fats, and proteins indirectly provide energy for physical movement. During exercise, the phosphagen system, lactic acid energy system, and aerobic oxidation system work together to supply energy for life activities. When energy supply is sufficient, muscle tissue functions normally, enabling the completion of exercise. However, as exercise duration increases or intensity rises, the body gradually relies on glycogen breakdown in the liver and muscles for energy. When the energy generated by glycogen fails to meet demand and is not replenished in time, peripheral fatigue occurs.

Research has found that the duration and intensity of physical exercise affect the rate of energy substance consumption, which in turn influences the onset of exercise-induced fatigue. During short-duration, high-intensity exercise, the ATP-CP system primarily provides energy, leading to a decrease in the levels of high-energy phosphates such as ATP and phosphocreatine (PCr) in the body. When fatigue sets in, the PCr content in muscles drops to 20% of its pre-exercise level. In contrast, during long-duration, low-intensity exercise, the aerobic oxidation system predominates in energy provision, with glycogen serving as the primary energy storage substance that is broken down to meet exercise demands and maintain blood glucose balance. Prolonged exercise significantly depletes glycogen, resulting in exercise-induced fatigue. Animal experiments have shown that when dogs exercise to the point of fatigue, their blood glucose levels decrease. However, administering adrenaline injections enhances the body's utilization of muscle glycogen, raising blood glucose concentrations and significantly restoring the dogs' exercise capacity. Additionally, fat hydrolysis generates a substantial amount of free fatty acids, and the accumulation of plasma free fatty acids promotes an increase in free tryptophan. Excessive amounts of tryptophan entering the brain elevate 5-hydroxytryptamine (5-HT) levels, inhibiting brain function and exacerbating central fatigue.

2.Accumulation of Metabolites

Compared to resting states, athletes consume more energy substances during high-intensity exercise and simultaneously produce more metabolites (such as lactic acid, NH4+, H+, etc.). If these metabolites are not promptly eliminated, they can block normal metabolic pathways, leading to a decline in muscle tissue's motor function and the onset of exercise-induced fatigue. During high-intensity exercise, athletes primarily rely on the lactic acid energy system for energy provision. Glycogen (glucose) undergoes anaerobic decomposition to produce lactic acid. As exercise intensity increases, lactic acid accumulates continuously in the body. During intense exercise, muscle lactic acid levels can reach 40 mmol/kg wet weight, and blood lactic acid levels can reach 18 mmol/L. The dissociation of lactic acid produces H+, which lowers the internal environment's pH value, inhibiting the activities of phosphorylase and phosphofructokinase, thereby suppressing the lactic acid energy system's energy supply, causing ATP deficiency and a sense of fatigue. Furthermore, brain cells are highly sensitive to changes in blood pH. A decrease in blood pH impairs brain cell function. Studies have confirmed that the higher the lactic acid content, the more pronounced the decline in the body's motor function and the longer the fatigue recovery period.

During muscle contraction during exercise, NH4+ (produced by AMP catalyzed by deaminase) is also generated. When ATP is consumed significantly, ammonia levels rise, promoting glycolysis and the production of lactic acid and H+. This combined effect of lactic acid and ammonia reduces bodily functions, leading to fatigue. Research shows that the production of NH4+ in the body is positively correlated with exercise intensity. During exercise, enhanced amino acid metabolism and increased adenosine diphosphate (ADP) concentrations in muscles lead to increased blood ammonia levels, inhibiting citrate dehydrogenase activity, affecting the body's energy metabolism and exercise balance, and even causing muscle spasms. Studies have confirmed that elevated blood ammonia levels can enter the brain tissue, exerting neurotoxic effects on brain cells, disrupting the balance between glutamate and γ-aminobutyric acid, and resulting in central fatigue.

3.Imbalance of Oxidation-Antioxidation System

Prolonged, high-intensity exercise can lead to an imbalance in the body's oxidation-antioxidation system, triggering oxidative stress symptoms. This results in the accumulation of intracellular free radicals, which induce oxidative damage to proteins and lipids, ultimately leading to exercise-induced fatigue. Glutathione (GSH) is a crucial antioxidant within the body, maintaining redox homeostasis by scavenging free radicals. Studies have shown that plasma GSH concentrations significantly decrease by 30% in athletes after marathon running and high-intensity cycling exercises.

The generation of free radicals during exercise is correlated with muscle contraction intensity. Transient or low-intensity muscle contractions induce the production of reactive oxygen species (ROS)/NO levels, which enhance the S-nitrosylation and S-glutathionylation of skeletal muscle contraction-related proteins such as Ca2+ release channel protein (RyR1) and troponin I, thereby improving myofibrillar calcium sensitivity and augmenting skeletal muscle contraction force. However, excessive ROS/NO production during exercise can lead to hyper-S-nitrosylation of RyR1, causing its dissociation from the subunit calstabin1. This inhibits myofibrillar calcium sensitivity, resulting in impaired skeletal muscle contraction function and reduced force output.

Furthermore, free radicals are also involved in substance transport. Under resting conditions, oxidative stress within the body remains at a low level, and moderate levels of free radicals contribute to vasodilation, enhancing the circulation of O2 and nutrients. However, excessively high levels of free radicals can inhibit vasodilation and reduce blood flow, leading to inadequate supply of O2 and nutrients to various tissues and organs such as skeletal muscles, the heart, skin, and the brain, thereby accelerating the onset of fatigue.

4.Ca2+ Metabolism Disorder

Ca2+ serves as a crucial regulatory factor in intracellular neuro-muscular signal transduction and exercise-induced fatigue resulting from aerobic activities. Research has revealed that the prolonged presence of high concentrations of Ca2+ in the cytoplasm can trigger apoptosis in normal muscle cells, and the disruption of intracellular calcium homeostasis ultimately leads to muscle fatigue and damage. Additionally, exercise elevates cytoplasmic Ca2+ concentrations, and mitochondria possess the capability to buffer and regulate these levels. However, during fatigue, lipid peroxidation reactions occur within the cellular membrane system, increasing the permeability of mitochondrial membranes to Ca2+. Consequently, a large influx of Ca2+ into mitochondria results in calcium paradox, where excessive accumulation of calcium ions inhibits the oxidative phosphorylation process within mitochondria. This decoupling of oxidative phosphorylation reduces ATP production, further disrupting cellular calcium ion metabolism, creating a vicious cycle that contributes to varying degrees of muscle fatigue and damage.

References

[1] Zhao Jing. Research Progress on Exercise Fatigue Mechanisms and Food-Derived Anti-Fatigue Active Ingredients [J]. Journal of Food Safety and Quality, 2021, 12(09): 3565-3571.

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

[3] Chen Hui, Ma Xuan, Cao Lihang, et al. Research Progress on Exercise Fatigue Mechanisms and Food-Derived Anti-Fatigue Active Ingredients [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.