Energy supply is essential for muscle contraction. The main sources of energy for muscle fibers are exhausted during the prolonged and intense exercise, including adenosine triphosphate (ATP), glycogen, and fats within the body system, thus leading to a lack of energy and aerobic capacity of skeletal muscle to complete the required muscle contraction or performed workload (Enoka and Duchateau, 2008; Ament and Verkerke, 2009). The energy materials are consumed differently based on different exercise conditions: The content of ATP and phosphocreatine (PCr) in skeletal muscle decreased during short-time high-intensity exercise, hence, directly resulting to exercise-induced fatigue; Carbohydrates are the primary consumed substrate during moderate exercise; Fats are the mainly consumed energy materials during long endurance exercise (Gastin, 2001; Shulman and Rothman, 2001; Skare et al., 2001). Exercise-induced fatigue also happens with the continuous energy consumption supplied from the ATP and the decrease of the phosphorylation of adenosine diphosphate (ADP) to ATP (Feng, 2003).

Metabolite accumulation theory holds that excess metabolites (such as lactate and amines, etc.) generated from the intense exercise and accumulated in skeletal muscle and blood, hence, resulting in fatigue. Lactate accumulation has been considered one of the most important causes of skeletal muscle fatigue (Westerblad et al., 2002). Long and high-intensity exercise may lead to the dysfunction of ATP production and utilization rates, which cause an increased ATP consumption accompanied by the accumulation of metabolic by-products, such as H⁺ and inorganic phosphate (Pi) (Wang et al., 2021b). The increased concentration of H⁺ (decreased pH) results in a glycolysis inhibition and ATP supply obstruction. The H⁺ accumulation also inhibits Ca²⁺ binding to troponin (Tn), consequently affect cross-bridge cycling and sarcoplasmic reticulum Ca²⁺ pumping, and ultimately contributes to muscle fatigue (Dutka and Lamb, 2000; Westerblad et al., 2002; Bandschapp et al., 2012; Xu et al., 2017). In addition, the concentration of ammonia raised in skeletal muscle during intense exercise. The increased ammonia activates phosphofructokinase and suppresses the oxidation of pyruvate to acetyl CoA, then promotes the production of blood and muscle lactic acids (BLA and MLA), blood urea nitrogen (BUN), creatine kinase (CK), and malondialdehyde (MDA) hence breaking homeostasis and causing fatigue (Takeda et al., 2011; Gough et al., 2021).

It has been demonstrated that excessive muscular exercise increases the production of reactive oxygen species (ROS) in body tissues and organs, including myocardial tissue, liver, skeletal muscles, and blood, thus causing an imbalance in the oxidation-antioxidant homeostasis in cells (Powers et al., 2020; Wang et al., 2021a). Low-to-moderate ROS levels are considered to be beneficial to the person’s physical performance, whereas high levels of ROS damage the membrane structure of cells or organelles by attacking biomacromolecules (lipids, proteins, and nucleic acids) (Vasilaki et al., 2017; Lu et al., 2021). In addition, the excessive exercise-induced ROS reduce the activity of skeletal sarcoplasmic reticulum calcium adenosine triphosphatase (Ca²⁺-ATPase), leading to the accumulation of Ca²⁺ in the cytoplasm, and influencing the excitation-contraction coupling of muscle fibers (Uyama et al., 1993). Consequently, the capacity for muscle contraction is reduced, which results in fatigue. Moreover, the elevated endogenous and exogenous ROS destroys mitochondrial functions and inhibits aerobic metabolism which causes exercise-induced fatigue (Cheng et al., 2016).

The prolonged and intense exercise triggers ROS production and oxidative stress and also causes acute and chronic inflammation, consequently leading to a drop in physical performance (Powers et al., 2011). After excessive exercise, pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels are increased (Liu et al., 2017; Medrado de Barcellos et al., 2021). It has also been reported that the elevated pro-inflammatory cytokines can activate the nuclear factor kappa-B (NF-κB) and generate a vicious circle of inflammatory response and mitochondrial dysfunction (López-Armada et al., 2013). The impaired mitochondria produce a greater amount of ROS, consequently, resulting in muscle strength decline and fatigue (Vargas and Marino, 2014).

Central inhibition plays an important role during exercise-induced fatigue and is considered a neurotransmitter mediated defense action (Tanaka et al., 2013). The nerve excitation from the skeletal muscle contraction constantly stimulates the corresponding neurons in the cerebral cortex and maintains excitement during exercise, thus, leading to a continuing consumption of ATP, fatty acids, PCr, and glucose (Hirvonen et al., 1992; Hargreaves, 2015). Subsequently, the cerebral cortex and central nervous system (CNS) switch from excitation to inhibition through the negative feedback regulation mechanism to prevent excessive consumption of energy materials, thus causing fatigue (Qiao et al., 2014).

The much-studied brain neurotransmitters, such as serotonin (5-HT) and dopamine (DA) were demonstrated to be dominant in accelerating fatigue during intense exercise (Roelands and Meeusen, 2010). 5-HT is a neurotransmitter synthesized from tryptophan (TRP), which can be transported through the blood-brain barrier with the aid of a specific carrier (Roelands and Meeusen, 2010). The concentration of the TRP in both plasma and brain raised, subsequently leads to an increase of 5-HT level in the brain during prolonged exercise (Hu Y. et al., 2015). It has been reported that the high concentration of 5-HT promotes lethargy and perceived exertion, thus inducing the exercise performance restriction and central fatigue (Meeusen et al., 2006). Hyperthermia is a critical limiting factor in long-term exercise, and it has been shown that DA affects core temperature regulation during exercise, which is recognized as being an important fatigue-related neurotransmitter (Zheng and Hasegawa, 2016; Wang et al., 2021b). In addition, an increase in serotonergic activity and a decrease in dopaminergic activity are also demonstrated to be responsible for the exercise-induced fatigue (Meeusen et al., 2007; Leite et al., 2010).

The endocrine disorder is another aspect of exercise-induced fatigue. It has been reported that the stress response is triggered by intense exercise, thus, activating the SA and HPA axes (Ulrich-Lai and Herman, 2009; Clark and Mach, 2016). Catecholamines (such as norepinephrine and epinephrine) and glucocorticoids were released into the circulation system, hence, resulting in an increased heart rate and blood pressure during the short-term moderate exercise. It has been reported that the key role of catecholamines is to regulate oxidative metabolism, lipoprotein metabolism, glycogen breakdown, and energy expenditure. Therefore, the concentration of catecholamines is positively correlated with the exercise ability during the short term. However, the increased exercise intensity and duration further leads to the decrease of energy substrate, the insufficiency of catecholamine receptors, and the weakening of receptor-mediated signals which result in the failure to enhance exercise ability through compensatory mechanism, although the concentration of catecholamines is still at a high level. Thus, the elevated level of catecholamines cannot enhance the long-term exercise ability, or can even weaken the exercise capacity (Zouhal et al., 2008). In addition, the exercise stress initially enhances the activation of the HPA and increases the cortisol concentration to regulate the energetic, metabolic, and immunologic processes (Grandys et al., 2016). The prolonged and high-intensity exercise initiates a continuous increase of cortisol which inhibits the HPA axis and decreases the level of serum testosterone, thus leading to a decline in physical performance.

Dendrobii Officinalis Caulis originated from the fresh or dried stems of Dendrobium officinale Kimura et Migo (Fam. Orchidaceae), which has been used as a precious TCM (Chinese Pharmacopoeia Commission, 2020). It is one of the well-accepted tonic medicines in China, and has also been broadly taken as dietary supplements to nourish the stomach, enhance body fluid production, tonify Yin, and clear heat of the internal organs (Zeng et al., 2018; Cao et al., 2020). D. officinale’s major bioactive components polysaccharide and flavonoids exhibited strong effects in improving exercise endurance, which is associated in the reduction of metabolite accumulation, increased activities of antioxidant enzymes, and gene and protein expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), nuclear factor-erythroid 2-related factor-2 (Nrf2), and superoxide dismutase 2 (SOD2) (Wei et al., 2017; Wang, 2021a). Studies also indicated that the D. officinale polysaccharide and flavonoids could enhance the cell viability of T/B lymphocytes, improve the immune system function, and regulate liver autophagy hence recovering from physical fatigue (Jiang, 2019; Wang et al., 2022a). The ethanol extract of D. officinale could improve fatigue resistance in exhausted swimming mice by protecting it against oxidative stress and enhancing the PGC-1α expression (Kim et al., 2020). In addition, the aqueous extract of D. officinale could effectively improve the endurance capability of mice against physical fatigue by regulating energy metabolism and nourishing muscle (Tang et al., 2014).

Lycii Fructus is the dried fruit of Lycium barbarum L. (Fam. Solanaceae), which has been used as traditional herbal medicine and food supplement for its restorative efficacy and benefiting to the liver and kidney, replenishing vital essence, and improving eyesight (Sze et al., 2008; Gao et al., 2017; Chinese Pharmacopoeia Commission, 2020). According to pharmacological research, L. barbarum polysaccharide (LBP) plays an important role as an antioxidant and anti-fatigue agent. It has been illustrated that LBP could enhance the exercise capacity by rising the activities of antioxidant enzymes, reducing free radicals and lipid peroxides, improving BLA tolerance of the skeletal muscle (Zhao et al., 2013; Hu X. Y. et al., 2015; Zhang Y. L. et al., 2015; Wei et al., 2020). Moreover, studies also showed that LBP could attenuate kidney injury by inactivating the NF-κB pathway, activating the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-NRF2) signaling, and reducing the release of pro-inflammatory cytokines (Wu et al., 2020). Liu et al., synthesized an LBP-SeNPs (selenium nanoparticles) product and demonstrated its activity in beating exercise-induced fatigue by up-regulating glycogen storage and antioxidant enzyme levels, as well as metabolic modulation activity (Liu et al., 2021). Furthermore, L. barbarum leaves showed similar anti-fatigue effects (Yue, 2016).

Epimedii Folium contains the dried leaves of Epimedium brevicornu Maxim., E. sagittatum (Sieb. et Zucc.) Maxim., E. pubescens Maxim., E. koreanum Nakai and relative plants in the same genus (Fam. Berberidaceae) with pharmacological effects in reinforcing the kidney Yang, strengthening the tendons and bones, and dispelling wind dampness (Chen et al., 2015; Chinese Pharmacopoeia Commission, 2020). Both of the aqueous and ethanol extracts of E. brevicornu could improve the endurance capability of the exercise-induced animal models by lowering the serum levels of BUN, BLA, and increasing the content of liver glycogen (Li et al., 2021b). The aqueous extract of E. davidii could increase the glycogen storage of the liver and muscle, and rise the serum testosterone level and hemoglobin concentration (Zhou et al., 2013). In addition, proteomic studies showed that the aqueous extract of Epimedium could affect the myosin light chain (MLC)1/3, heat shock protein 27 (HSP27), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Troponin I fast (TnIf) of gastrocnemius muscle to exert their anti-fatigue effects in overtraining rats (Sun, 2014). Flavonoids are the major components of Epimedium with strong anti-fatigue activity: icariin and icariside I could reduce BUN and LDA levels, reduce exercise-induced oxidative stress markers (ALT, AST, and MDA) (Shang et al., 2012; Chen and Wei, 2013; Guo, 2014; Li et al., 2014). Moreover, the icariin-zinc complex showed similar effects in relieving exercise-induced fatigue (Zhang J. et al., 2021).

Cistanches Herba, also called “Desert Ginseng”, which originated from the dried fleshy stem with scaly leaves of Cistanche deserticola Y. C. Ma or C. tubulosa (Schenk) Wight (Fam. Orobanchaceae). It is another herbal medicine widely used in China and other Asian countries because of its efficacy in nourishing the kidney Yang, benefiting blood and essence, and moistening intestines to easily pass stool (Chinese Pharmacopoeia Commission, 2020). It has been reported that the ethanol extract of C. deserticola presented positive effects on the oxidative stress markers and the activity of antioxidant enzymes in myocardial mitochondria in exercise-induced fatigue rats, which was conducive to effectively inhibiting the oxidative damage of mitochondrial caused by excessive exercise (Gao et al., 2011; Zhou et al., 2012). The total polyphenols, glycosides, and sugar of the Cistanche have been demonstrated to improve the glycogen levels of the liver and muscle, increase the activity of antioxidant enzymes, and decrease the BLA, BUN, MDA, and CK levels (Wang, 2020c; Luan, 2020). The Cistanche phenylethanol glycosides and gardenia yellow pigment mixture could relieve the hypoxic exercise fatigue by improving the activities of antioxidant and metabolic enzymes, reducing the expression of apoptotic proteins, and lowering the AMP-activated protein kinase (AMPK) and NADPH oxidases 2 (Nox2) levels in hypoxic exhaustive swimming rats (Li et al., 2021a). The oligosaccharides of C. tubulosa have been found to exert anti-fatigue effects by reducing the accumulated harmful metabolites, maintaining the stability of hormonal levels related to the HPA axis, and enhancing the glycogen storage (Wang, 2020a). More frequently used Yin nourishing and Yang supporting TCMs showing relieving effects on exercise-induced fatigue are listed in Supplementary Table S1.

Ginseng Radix et Rhizoma (Panax ginseng C. A. Mey., Fam. Araliaceae), one of “the Four Pillars” of TCMs, has long been used as a medicinal and edible food for nutrient supplements and treating various diseases given its extradentary effects in reinforcing vital energy (Qi) (Chinese Pharmacopoeia Commission, 2020). Recent studies showed that the ginsenosides and ginseng polysaccharides could prolong the exercise time of different animal models: these bioactive ingredients could decrease BUN, BLA, LDA, CK, and MDA levels, increase the liver and muscle glycogen contents, enhance SOD, catalase (CAT), and GSH-Px activities, which effectively assist the body in removing oxygen free radicals produced by strenuous exercise, protecting the mitochondrial membrane from the lipid peroxidation and maintaining its integrity (Feng et al., 2010b; Jiao et al., 2021; Kong et al., 2021). The total ginsenosides could protect the excessive exercise-induced kidney injury by down-regulating the protein expression caspases-3 and increase the level of hypoxia inducible factor-1 (HIF-1α) expression (Wang et al., 2014). 20 (S)-protopanaxadiol was found to delay the exercise-induced LA accumulation by directly activating the activity of creatine kinase isoenzyme-3 (Chen F. et al., 2020). Metabonomic research indicated that ginsenoside Rh1 supplementation could reduce the α-D-glucosamine 1-phosphate content and regulate the tricarboxylic acid cycle in relieving physical fatigue (Wang, 2020b). It also has been reported that ginseng polysaccharides could restore the erythrocyte function injury caused by excessive exercise through increasing the contents of ATP, ATPase, and sialic acid in rat serum after exhaustive swimming, restoring the activities of Na⁺/K⁺-ATPase, and Ca²⁺/Mg²⁺-ATPase in a dose-dependent manner (Yang et al., 2019). In addition, ginsenosides could also reduce the contents of gamma-aminobutyric acid (GABA) and 5-HT, and increase the acetylcholine chloride (Ach), NE, and DA levels of the CNS (Feng et al., 2010a; Chen and Li, 2011), inhibit the expression of pro-inflammatory cytokines such as TNF-α in relieving inflammatory responses, and reshape the gut microbial ecosystem in alleviating exercise-induced fatigue (Zheng et al., 2021; Zhou et al., 2021).

Rhodiolae Crenulatae Radix et Rhizoma (Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba, Fam. Crassulaceae) and its homologues from the same species are famous for their function of invigorating Qi and promoting blood circulation in both TCM and Tibetan medicine (Chinese Pharmacopoeia Commission, 2020; Wang et al., 2022b). Different extracts of R. crenulate, R. rosea, and R. sachalinensis have been found to reduce exercise-induced fatigue and oxidative stress by lowering the levels of BUN, MDA, CK, and LA, and increasing the activities of SOD, GSH-Px, CAT, and T-AOC to exert definite anti-exercise-induced fatigue effects (Zhou et al., 2010; Li, 2013; Jówko et al., 2018; Hou et al., 2020). In addition, the commercial R. crenulata oral liquid could alleviate the deficiency of energy supply by improving the levels of liver and muscle glycogen, and enhancing the activities of the Ca²⁺-ATPase and Na⁺/K⁺-ATPase to stabilize the ATP synthesis and storage. It could ameliorate exercise-induced fatigue by inhibiting mitophagy via suppressing the PINK1/Parkin signaling pathway (Hou et al., 2020). In addition, salidroside showed activity to increase the levels of the DA and NA and to decrease the 5-HT, and the 5-hydroxyindoleacetic acid (5-HIAA) contents to maintain the steady state of neurotransmitters in brain tissue of the exercise-induced fatigue mice (Gai and Zheng, 2016).

Astragali Radix (AR), the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or A. membranaceus (Fisch.) Bge (Fam. Leguminosae), is one of the essential and commonly used TCMs to invigorate Qi and promote Yang (Chen Z. et al., 2020; Chinese Pharmacopoeia Commission, 2020). All of the AR’s aqueous and ethanol extracts, and the total astragalosides and flavonoids exhibited an ability in improving the endogenous antioxidant capacity by reducing the levels of oxidative stress markers (BUN, MDA, LA, CK, and LDH), improving the ability of antioxidant enzymes (SOD, POD, Ca²⁺-ATPase), enhancing the regeneration of ATP and glycogen levels (Li et al., 2010; Yeh et al., 2014; Zhang G. et al., 2015). Li et al. demonstrated that the aqueous extract of AR remarkably increased the oxygen-carrying capacity and the hemoglobin (HG) content in hypoxic exhausted mice (Li et al., 2012a). Feng et al. reported that the anti-fatigue effect of total astragalosides may be linked to the improvement of hippocampal neuron injury by elevating the activities of total antioxidant capacity (T-AOC) and acetylcholinesterase (TchE), and reducing the positive cells of caspase-3 (Feng et al., 2014). Interestingly, the AR acupoint injection could alleviate exercise-induced fatigue caused by the hyperactivity of the HPA axis and maintain the balance of Th1 and Th2 cytokines (Li et al., 2012b; Li et al., 2012c). More frequently used Qi promoting and blood circulating TCMs showing relieving effects on exercise-induced fatigue are listed in Supplementary Table S2.

Portulacae Herba is the aerial part of Portulaca oleracea L. (Fam. Portulacaceae) which is a medicine and food homologous drug that clears internal heat and removes toxin, cools blood and stops bleeding (Chinese Pharmacopoeia Commission, 2020; Qin et al., 2020). It has been reported that the commercial extract of P. oleracea could extend exhaustive swimming time of mice, decrease the accumulation of BLA in skeletal muscle and the activity of LDH (Liu J. et al., 2010; Liu Z. et al., 2010). Xu and Shan illustrated the anti-fatigue effects of P. oleracea polysaccharides in the rotarod test and forced swimming animal models by reducing the levels of BLA and BUN, and elevating the contents of liver and muscle glycogen (Xu and Shan, 2014).

Puerariae Lobatae Radix (Pueraria lobata (Willd.) Ohwi, Fam. Leguminosae) has been widely planted in China and used as a medicine and food for a long time because of its healing effects in relieving muscles to expel heat, engendering liquid, and relieving thirst (Chinese Pharmacopoeia Commission, 2020; He et al., 2022). Puerarin, a kind of isoflavone glucosides, was elucidated to reduce NO content in the hippocampus, inhibit iNOS mRNA, and cGMP levels of exercise-induced fatigue rats (Guo and Xi, 2012). Besides, puerarin showed a distinctive function in improving the hemorheology of exercise-induced fatigue rats and effectively enhances the exercise capacity (Gong et al., 2012). Moreover, the puerarin supplementation remarkably decreased the apoptosis rate of hippocampal neurons by inhibiting the expression of P53 and up-regulating the Bcl-2 mRNA in swimming-exhausted rats, thus promoting fatigue recovery (Cheng and He, 2010). It also has been reported that the total flavonoids of P. lobata reduced skeletal muscle oxidative stress and improved the fatigue syndrome by suppressing p38 MAPK/ERK signaling pathway (Zhu, 2020). The total flavonoids of P. lobata showed a protective effect on brain tissue of exercise-induced fatigue rats through down-regulating the expression of β-catenin, glycogen synthase kinase 3β (GSK-3β), signaling transducer and activator of transcription 3 (STAT3), and inhibiting the accompanying inflammatory response (Jiang et al., 2020; Mo et al., 2020).

Taraxaci Herba is the entire plants of Taraxacum mongolicum Hand. Mazz., or T. borealisinense Kitam. or other sibling plants of genus Taraxacum (Fam. Compositae) (Chinese Pharmacopoeia Commission, 2020). It is frequently used as a heat-clearing herb because of its medicinal and edible values (Chinese Pharmacopoeia Commission, 2020). The polysaccharides and the aqueous extract of Taraxacum have been found to exert great anti-fatigue effects by improving the muscle and liver glycogen contents, and lowering the BLA, BUN and TG levels in exercise-induced fatigue mice (Liang et al., 2011; Zhang and Chen, 2011; Lee et al., 2012; Hu, 2014). Furthermore, the aqueous extract of T. officinale exhibited a potent immune-enhancing effect through increasing the synthesis and release of several cytokines (such as TNF-α, IL-12p70, and IL-10) and immunoactive mediators in the primary cultured peritoneal macrophages. The immunopotentiation of T. officinale may be conducive to improving the immunosuppressive state caused by exercise-induced fatigue (Lee et al., 2012).