Impacts of Green Tea on Joint and Skeletal Muscle Health: Prospects of Translational Nutrition

Osteoarthritis and sarcopenia are two major joint and skeletal muscle diseases prevalent during aging. Osteoarthritis is a multifactorial progressive degenerative and inflammatory disorder of articular cartilage. Cartilage protection and pain management are the two most important strategies in the management of osteoarthritis. Sarcopenia, a condition of loss of muscle mass and strength, is associated with impaired neuromuscular innervation, the transition of skeletal muscle fiber type, and reduced muscle regenerative capacity. Management of sarcopenia requires addressing both skeletal muscle quantity and quality. Emerging evidence suggests that green tea catechins play an important role in maintaining healthy joints and skeletal muscle. This review covers (i) the prevalence and etiology of osteoarthritis and sarcopenia, such as excessive inflammation and oxidative stress, mitochondrial dysfunction, and reduced autophagy; (ii) the effects of green tea catechins on joint health by downregulating inflammatory signaling mediators, upregulating anabolic mediators, and modulating miRNAs expression, resulting in reduced chondrocyte death, collagen degradation, and cartilage protection; (iii) the effects of green tea catechins on skeletal muscle health via maintaining a dynamic balance between protein synthesis and degradation and boosting the synthesis of mitochondrial energy metabolism, resulting in favorable muscle homeostasis and mitigation of muscle atrophy with aging; and (iv) the current study limitations and future research directions.


Prevalence of Osteoarthritis and Sarcopenia
Osteoarthritis (OA) and sarcopenia (SC), two major aging-related joint and skeletal muscle diseases, are prevalent among the elderly population and interact closely during the complex biological process Table 1. Comparison of tea leaves processing and chemical composition among green tea, black tea, and Yerba Mate tea [57].

Green Tea Black Tea Yerba Mate Tea
Processing of tea leaves Steamed or pan-fried; not oxidized.
Withered and fermented and not blanched before drying; oxidized. Tea (Camellia sinensis), especially green tea, which has catechins as the major active ingredient (12-24% dry weight), contains a large number of phenolic hydroxyl groups (-OH). The four monomers of catechins include epigallocatechin gallate (EGCG), epicatechin (EC), epigallocatechin (EGC), and epicatechin gallate (ECG). Green tea and its major bioactive component of the polyphenolic fraction of green tea, EGCG, have been suggested to be capable of protecting against cartilage loss and reducing the progression of OA in the past decade. Recently, green tea catechins (GTCs) demonstrated the potential to re-establish homeostasis of skeletal muscle cells and even attenuate muscle mass loss. In this review, we summarize the state of knowledge of laboratory preclinical research and limited human studies assessing the effects of green tea and EGCG on joint and skeletal muscle, along with a discussion of future directions in translational research. Table 2 summarizes the effects of green tea and EGCG on joint health based on in vitro (cell and tissue explant), in vivo (animal), and human studies. Adcocks et al. first reported that EGCG, rich in antioxidant capacity, protects the cartilage matrix (proteoglycan and type II collagen) from degradation in bovine cartilage explants and human OA cartilage explants [58]. In follow-up studies, other authors corroborated that EGCG reduced the release of glycosaminoglycans (GAG, a component of cartilage matrix) and type II collagen from human cartilage explants [59,60] and selectively inhibits the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)1, ADAMTS4, and ADAMTS5 [61,62]. The chondroprotective effects of EGCG are due to EGCG's anti-inflammatory action, as evidenced by inhibiting the expression of proinflammatory genes (i.e., COX-2, TNF-α, MMP-1, MMP-13, iNOS, and ADAMTS5) [59,[62][63][64][65][66][67][68][69]. Such anti-inflammatory effects of EGCG are mediated by the suppression of NF-κB signaling cascades [59,63,66,[69][70][71][72] and MAPK including p38-MAPK, Erk1/Erk2 [63,65,71,73], activator protein-1 (AP-1) [59,70], c-jun N-terminal kinase (JNK) activation, and IKKβ kinases phosphorylation [59,64,73] in chondrocytes as a result of the decreased differentiation of chondrocytes [74]. With respect to synoviocytes, Zheng et al. recently reported that EGCG-glucosamine nanoparticles exhibit antiarthritic activity in human-fibroblast-like synoviocytes-OA cells due to EGCG's anti-inflammatory action [75]. Furthermore, EGCG has been used to stabilize an osteochondral xenograft prior to graft implantation for the repair of a defect [76]. Elder et al. also demonstrated that EGCG treatment resisted an osteochondral xenograft from collagenase degradation via increased collagen crosslinking as a result of the restored mechanical properties of osteochondral xenograft [76].

Cell and Tissue Explant Studies
In addition to EGCG's anticatabolic effects on OA, EGCG also has anabolic effects on OA. Andriamanalijaona et al. reported that EGCG stimulated the IL-1β-induced expression of transforming growth factor (TGF)-β1, TGF-β2, and its receptors TGF-βR1 and TGF-βRII in bovine articular chondrocytes, resulting in enhanced type II collagen and aggrecan core protein synthesis in human articular chondrocytes [63]. Huang et al. showed EGCG supplementation stimulates chondrocyte growth and the synthesis of cartilage extracellular matrix by enhancing the gene expression of aggrecan, collagen type II, and SRY-Box Transcription Factor (SOX9) and suppressing the gene expression of collagen in primary rabbit articular chondrocytes [74]. Jin et al. recently demonstrated that EGCG addition to hyaluronic-acid-based hydrogel synergistically stimulates chondrogenic regeneration by increasing the gene expression of collagen type II, SOX9, and aggrecan in primary porcine 3D encapsulated OA chondrocytes [62]. Table 3 summarizes the effects of ECGC on selected miRNA expressions in human or murine chondrocytes. MicroRNAs (miRNAs) are endogenous and noncoding single-stranded RNAs with a profound role in gene regulation at post-transcriptional levels [77]. miRNA (also named miR) regulation and expression have become an emerging field in determining the mechanisms involved in a variety of inflammation-mediated diseases, including OA. In OA, specific miRNAs have been identified and linked to OA risk factors, such as inflammation, obesity, autophagy, and imbalanced cartilage homeostasis [77]. miRNAs are able to modulate most OA relevant genes in stimulated human OA chondrocytes [59,67,[78][79][80][81][82][83][84][85]. For example, miR-27b is a direct regulator of MMP-13 in human OA chondrocytes [78]. hsa-miR-26a-6p regulates the expression of iNOS via the activation of NF-κB signaling pathways [83]. Furthermore, miRNAs including miR-27b [79], miR-26a-5p [80], hsa-miR-199a-3p [67], miR-127-5p [81], miR-602 [82], miR-608 [82], miR-320 [83], miR-558 [84], miR-9 [85], and miR-381 [86] also play significant roles in regulating key inflammatory genes in the development of OA. Rasheed et al. first demonstrated that EGCG inhibits COX-2 mRNA/protein expression by upregulating miRNA hsa-miR-199a-3p expression in IL-1β-induced human OA chondrocytes [67]. In a study on a human miRNA microarray of 1347 miRNAs, EGCG upregulated the expressions of 19 of them (such as hsa-miR-140-3p) and downregulated the expressions of 17, whereas the expressions of the remaining miRNAs remained unchanged in IL-1β-induced human OA chondrocytes [87]. The IL-1β-induced expression of ADAMTS5 correlated with the downregulation of hsa-miR-140-3p, and EGCG-induced coregulation between ADAMTS5 and hsa-miR-140-3p became reversed in OA chondrocytes transfected with anti-miR-140-3p [87]. Zhang et al. recently reported that the pretreatment of green tea polyphenols mitigates lipopolysaccharide-induced inflammatory response along with suppression of MAPK and NF-κB pathways by positively regulating miR-9 (an anti-inflammatory regulator) expression in murine chondrogenic ATDC5 cells [71]. These findings suggest that the chondroprotective roles of green tea and EGCG may be associated with EGCG's ability to suppress inflammatory response by modulating miRNAs expression [87].

Animal Studies
Green tea and EGCG have been shown to protect cartilage degradation in a variety of animal OA models. In a study using a mouse model with collagen-induced arthritis, Haqqi et al. first reported that the supplementation of green tea polyphenols in the drinking water significantly reduced the incidence of arthritis in mice, as shown by (i) decreased type II collagen-specific IgG levels, (ii) the reduced expression of proinflammatory genes (COX2, TNF-α, IFN-γ), (iii) decreased joint infiltration by TNF-α and IFN-γ-producing cells, and (iv) increased neutral endopeptidase activity in arthritic joints [88]. In a study using a mouse model with intra-articular carrageenan-induced OA, compared with control, the GTE-treated group demonstrated lower levels of lipid peroxides, NO, and total thiols in the plasma, as well as reduced inflammatory cells infiltrating the synovial membrane [89]. In a study of mice with post-traumatic OA by the destabilization of the medial meniscus (DMM), Leong et al. reported that EGCG significantly slows progression in early-and midstage OA development, as indicated by lower OARSI scores and higher locomotor behavior [90]. EGCG-treated post-traumatic OA mice exhibited a reduced degradation of both type II collagen and aggrecan in the articular cartilage matrix by suppressing the gene expression of MMP-1, -3, -8, and -13, ADAMTS5, IL-1β, and TNF-α, and inducing the gene expression of MMP-repressing transcriptional regulator CITED2 in the articular cartilage [90]. Recently, in a study using a mouse model with surgically induced OA, Jin et al. reported that treatment with crosslinking of EGCG into hyaluronic acid (a major component of the cartilage extracellular matrix) hydrogel protects cartilage from physical abrasion in arthritic joints, as demonstrated by mitigated loss of glycosaminoglycan and type II collagen as well as reduced expression of collagen I and X [62].

Rodent Studies
The use of GTE has been shown to improve oxidative state and skeletal muscle health (e.g., strength, morphological integrity, and the number of muscle stem cells). For example, in a dystrophic C57BL/10-mdx (mdx) model, the abnormally high ROS results in severe muscle damage and affects muscle integrity (i.e., membrane stability) [96]. Administering EGCG (5 mg/kg, 4×/week for eight weeks) resulted in less fibrosis and fewer necrotic myofibers in mice with muscular dystrophy [97]. Similarly, supplementing the diet with 0.01% to 0.25% of GTE for 4-5 weeks increased the antioxidant potential in the plasma [98] and reduced necrosis in the extensor digitorum longus (EDL) muscles of mdx mice [98,99]. Moreover, EGCG supplementation decreased protein carbonyl content, a marker of oxidative stress, in aged (34 months) male albino Wistar rats [100]. The findings that GTE supplementation enhances total antioxidant potential (i.e., GSH-Px, SOD, CAT) and lowers carbonylated protein levels in skeletal muscle are consistent in a variety of rodent models including BALB/c mice, female Sprague-Dawley rats, and male Kunming mice [101][102][103]. Interestingly, in male ICR mice, tannase-converted GTE (80 µM) with greater antioxidant capacity increased antioxidant enzyme SOD and CAT content [104].

Human Studies
In male soccer players and sprinters, GTE supplementation (450 mg/d and 980 mg/d) for four to six weeks resulted in an increase in systemic total antioxidant capacity and a decrease in MDA (a marker for oxidative stress) [105,106]. In response to a bout of exercise, Panza et al. showed that a week of GTC supplementation (2 g of leaves in 200 mL of water) three times per day prior to a single bout of resistance exercise protected against the systemic oxidative exercise-induced damage in weight-trained men [107]. Furthermore, combining GTE (250 mg/d) supplementation with endurance training for four weeks increased systemic total antioxidant capacity and reduced MDA production but not with GTE supplementation or endurance training alone [108]. However, Silva et al. reported a change in only creatine kinase levels following a 15-day GTE supplementation in untrained men [109]. These results from human studies suggest that GTE supplementation may not affect the basal oxidative state but may reduce exercise-induced oxidative stress.

Effect of GTE on Inflammation of Skeletal Muscle Animal studies
GTE has been shown to reduce proinflammatory cytokines in skeletal muscle with elevated inflammatory signaling. Female Sprague-Dawley rats fed a high-fat diet (aimed to induce obesity) supplemented with GTE (0.5% wt/vol GTE for 12 weeks) showed lower serum concentrations of IL-1α, IL-2, GM-CSF, IFN-γ, and TNF-α compared to a high-fat diet without GTE [102]. Similarly, male Wistar rats fed a high-fat diet supplemented with GTE (1 g/kg GTE for six weeks) had a lower intramuscular TNF-α and COX-2 RNA expression than a high-fat diet alone [110]. Similar results were reported in studies using the RNAseq technique, where inflammation-related genes (Cd163, Cfh, Il33, C3, Hp, Lbp) were downregulated in C57bL/6J mice fed a high-fat diet supplemented with GTE (5% wt/wt GTE for eight weeks) than those fed a high-fat diet alone, and the addictive effect of exercise on GTE reduced inflammation [111]. Mice with obesity induced by a high-fat diet treated with endurance training (15 min of treadmill running 6×/week for eight weeks) along with GTE supplementation showed a greater decrease in inflammation-related genes (i.e., Cd163, Cfh, Il33, C3, Hp, Lbp) than those treated with GTE or endurance exercise alone [111]. In addition, male ICR mice supplemented with GTE (0.5% wt/wt for three weeks) prior to a bout of exercise causing muscle damage showed a lower TNF-α, IL-1b, and MCP-1 RNA expression than mice with exercise-induced muscle damage alone [112]. To further investigate whether the decrease in inflammatory cytokines is regulated by the upstream regulator (i.e., NF-κB), Zhang et al. reported an increase in phosphorylated IkBα (NF-κB inhibitor) expression, which, at least in part, explained their observation of decreased inflammatory-related genes in mice fed a high-fat diet supplemented with GTE [111]. Such results are supported by a decreased intramuscular NF-κB protein content in male C57BL/6 mice with LLC cells tumor treated with GTE supplementation at 0.6 mg/mouse for 12 days [113] and mdx mice treated with GTE supplementation [114]. These results have consistently demonstrated the anti-inflammatory effect of GTE via upstream regulation, albeit they are limited to rodent models. In the future, a human study is needed to further elucidate the anti-inflammatory properties of GTE, considering chronic low-grade inflammation is a major attributing factor for the development of sarcopenia.

Effect of GTE on Autophagy in Skeletal Muscle
Autophagy promotes a muscle mass increase in SC muscle models [28]. A loss in skeletal muscle mass during aging could be attributed to the intracellular accumulation of damaged proteins and organelles as a result of reduced autophagic activity [115]. Emerging evidence suggests that GTE supplementation may reverse the suppression of autophagy signaling in aged skeletal muscles [51,116,117]. In in vitro studies, GTE initiated upstream signaling (increased FoxO3 nuclear accumulation and AMPK activity) [118] and phagophore initiation (i.e., decreased inhibit beclin-1 inhibitor) [119] for autophagy. GTE supplementation (polyphenol blend; 40% catechins, 3-8% EGCG) for 28 days suppressed an increase in Bcl-2 (beclin-1 inhibitor) and BAD (autophagy inhibitor) due to muscle damage in men [120]. It is noteworthy that incubating C2C12 muscle cells with 25 µM of EGCG and 300 µM of H 2 O 2 for 48 h resulted in a reversion of AMPK activity compared to a decreased AMPK activity with EGCG treatment alone [93]. Wang et al. suggest that in healthy muscle cells, EGCG effectively reduces ROS such that the induction of autophagy may not be warranted. However, in muscle cells containing excessive ROS (i.e., in SC muscle), the antioxidative properties of EGCG alone may not be sufficient to reduce the ROS burden, requiring increased autophagy activity [93]. On the other hand, Mirza et al. reported an overall decrease in protein degradation rates following EGCG (10 µM) treatment [121]. Future studies are required to fully elucidate the effect of GTE on autophagy in SC muscle models.
Maintaining mitochondrial quality is linked to skeletal muscle health [122] and improved exercise tolerance [123]. Mice treated with EGCG had an increased expression of mitophagy (PINK1, UCP2) and autophagy (LC3B:LC3A, ATG16L, DAPK, TM9SF1, and PIM2) in skeletal muscle [45,124], but other studies showed inconsistent results [125,126]. EGCG supplementation was shown to mitigate the hindlimb suspension-induced decrease in mitophagy [45]. Takahashi et al. reported that in the absence of exercise, GTE supplementation might help mitigate the age-related reduction in autophagic activity [45]. Furthermore, supplementing GTE prior to exercise could potentially help reduce the negative effect of exercise-induced oxidative stress in the older population [45]. Although no study has directly examined the effect of EGCG on the crosstalk between ROS content, autophagy, and mitophagy activity related to skeletal muscle heath, published results linking the increase in autophagy to improved muscle mass suggest that EGCG could delay muscle mass loss in SC-like rats [127], the attenuation of skeletal muscle mass loss in mice with Lewis lung carcinoma cachexia [98], and enhance muscle function in mice with Duchenne muscular dystrophy [113]. This may, at least in part, be related to EGCG-induced autophagy of skeletal muscle.

Effect of GTE on Mitochondria-Related Metabolism in Skeletal Muscle
Besides regulating mitochondrial quality, increasing the generation of mitochondria (mitochondria biogenesis) is also an important factor for skeletal muscle health and improving exercise capacity. Mitochondrial biogenesis via peroxisome-proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling is one of the most important molecular adaptations from endurance exercise. In rodent studies, GTE supplementation with endurance exercise increased PGC-1α mRNA expression compared to GTE supplementation or endurance exercise alone [128,129]. Incubating C2C12 muscle cells with EGCG (25 µM) for 48 h showed a decrease in PGC-1α protein content [93]. However, the relationship between GTE and mitochondrial biogenesis in skeletal muscle has not been comprehensively elucidated.
Metabolically, GTE supplementation has been shown to increase mitochondrial enzymes involved in fatty acid oxidation. Sae-tan et al. reported that EGCG supplemented in a high-fat diet for 16 weeks increased mRNA expression of medium-chain acyl coA decarboxylase (MCAD) involved in mitochondrial fatty acid β-oxidation in the skeletal muscle of obese mice [125]. The fatty acid metabolism of skeletal muscle appeared to be further improved by combined GTE supplementation and exercise [128,129]. For instance, Murase et al. reported that senescence-accelerated mice treated with GTE supplementation together with treadmill running for 10 weeks achieved a greater increase in skeletal muscle fatty acid β-oxidation than those treated with either the GTE supplement or treadmill running alone, as shown by an increase in mRNA levels of mitochondria-related metabolism molecules such as mitochondrial cytochrome b, mitochondrial cytochrome c oxidase II, III, and IV [129]. Sae-Tan et al. corroborated the above result that the combination of GTE supplement and exercise increased the expression of mitochondria-related metabolism molecules in skeletal muscle of obese mice compared to those treated with GTE supplement or exercise alone [128].
The GTE-induced improvement of mitochondrial capacity to metabolize fatty acid may also translate into enhanced exercise capacity. In both aging and obese rodent models, two to four weeks of endurance training (swimming and running) combined with GTE supplementation increased exercise time to exhaustion and the total distance covered compared to either GTE or treadmill running alone [130][131][132][133]. The improvement in exercise capacity was attributed to increased reliance on fatty acid metabolism including β-oxidation activity, plasma free fatty acid concentration, and fatty acid translocase [130,131]. In an aged mice model, supplementing GTE for 10 weeks maintained endurance capacity compared to young mice [129]. Besides endurance capacity, five weeks of GTE supplementation in the standard diet provided 30 to 50% greater residual force production in mdx mice than those without GTE, suggesting that GTE was able to mitigate loss in force production without exercise training [98]. The above results suggest that EGCG treatment contributes to the improvement of mitochondrial health and efficacy in rodent models. Similarly, in humans, GTE (500 mg/d for eight weeks) supplementation was shown to increase reliance on fat oxidation during 60 min cycling exercise at 75% VO2max [134].

Effect of GTE on Satellite Cells, Muscle Damage, and Recovery
Satellite cell, a skeletal muscle stem cell, is important for muscle regeneration and repair [135]. Age-related decline in satellite cell number (i.e., stem cell pool) and disrupted myogenic progression (activation, proliferation, and differentiation) are among many factors that cause a decline in muscle mass and muscle regeneration capacity [136]. Incubating C2C12 muscle cells with EGCG or GTE resulted in an increase in MyoD (indicator of proliferation) as well as Myf5 and myogenin (indicator of differentiation) gene expression [137,138]. Similarly, supplementing aged mice with tannase-converted GTE increased MyoD, Myf5, and myogenin and decreased myostatin (a protein that suppresses satellite cell proliferation and differentiation) expression in skeletal muscle development [104].
Morphologically, EGCG supplementation was linked to an increased myonuclei number, myotube formation, cross-sectional area, and muscle mass through in vitro and rodent model studies [114,127,[139][140][141]. There was no difference in lean mass gain between EGCG (250 mg/kg) alone and EGCG running for 39 days in adult mice [142]. In a limb-immobilization model, aged rats were treated with a GTE supplement (50 mg/kg) for seven days prior to 14 days of hindlimb suspension in one group, and another group received the same treatment plus a subsequent 14 days of ambulation. Both groups demonstrated increased satellite cell activation and muscle cross-sectional area [143]. Although the above results represent strong evidence with regard to the potential benefits of GTE in SC myogenic progression and muscle regeneration, future human research in this area is warranted. Table 4. Summary of studies on the effects of green tea and EGCG on skeletal muscle health.

Cellular Studies
Babu, 2017, [95] Model: C2C12 skeletal muscle cells Treatment: Pretreated with or without GTE (20, 40, and 80 µg/mL) for 2 h followed by with or without citrinin treatment (0, 25 [110] Model: Male Wistar Rat Treatment: Rats were fed a high-fructose diet (induced insulin resistance and oxidative stress) and green tea solid extract (EGCG 12.75%) (1 or 2 g/kg) diet for 6 weeks Compared to the control (high-fat alone), the GTE group showed: ↑ mRNA expression of anti-inflammatory tristetraproline family in liver and muscle ↓ mRNA expression of proinflammatory genes in liver and muscle Table 4. Cont.

First Author, Year, Citation Experimental Design and Treatments Effects of Green Tea or EGCG
Chen, 2020, [145] Model: Male BALB/c mice Treatment: Fed a control diet (no GTE) or GTE (0.2 g/kg) and/or endurance exercised (treadmill running) for 8 weeks Model: C2C12 skeletal muscle cells Treatment: Pretreated with or without (control group) GTE (0.01%) and then exposed to ammonium chloride (5 mM Model: BALB/c mice Treatment: Fed a control diet (no GTE) or GTE (0.2-0.5%) for 10 weeks and then endurance exercised (swimming until exhaustion) Compared to the control group, the GTE group showed: ↑ Swimming times to exhaustion (8-24%) ↑ β-oxidation activity, fat oxidation, and plasma free fatty acid concentration ↓ Respiratory quotient and plasma lactate concentration ↑ Fatty acid translocase/CD36 mRNA expression Murase, 2006, [131] Model: BALB/c mice Treatment: Exercised with or without GTE (0.2-0.5%) for 10 weeks and then endurance exercised (treadmill running until exhaustion) Compared to the control (exercise only) group, the GTE group showed: ↑ Running times to exhaustion 30% ↓ Respiratory exchange ratio, malonyl-CoA content, and plasma lactate concentration ↑ β-oxidation activity, muscle glycogen content, and plasma free fatty acid concentration Murase, 2008, [129] Model: Senescence-accelerated prone mice Treatment: Fed a control diet (no GTE) or GTE (0.35%, EGCG 41%) for 10 weeks and/or endurance exercised (treadmill running) Compared to the control group, the GTE group showed: Maintained endurance capacity ↓ Oxidative stress Compared to the control group, the GTE with the exercise group showed: ↑ Oxygen consumption, fatty acid β-oxidation, mitochondria-related mRNA expression    Figure 1 illustrates the potential effects of GTCs on skeletal muscle. GTCs have been shown to effectively suppress inflammation and oxidative stress and promote autophagic and mitophagy activities. Improving the quality of mitochondria (decreased ROS leakage and improved oxidative metabolism) and potentially increasing mitochondrial biogenesis could provide machinery for muscle cell growth and regeneration capacity. Although these potential benefits of GTCs on skeletal muscle health need to be further elucidated, GTCs are promising dietary nutritional supplements capable of maintaining muscle homeostasis and combating disuse muscle atrophy with aging. target of rapamycin; MuRF-1, muscle RING-finger protein-1; Myf5, myogenic factor 5; MyoD, myoblast determination protein 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF-1, nuclear respiratory factor 1; PGC-1α, Pparg coactivator 1 alpha; PIF, proteolysisinducing factor; PIM-2, proviral Integrations of Moloney virus 2; Pink1, PTEN-induced kinase 1; PPAR-γ, peroxisome proliferator-activated receptor gamma; S6K, ribosomal protein S6 kinase beta-1; SDH, succinate dehydrogenase; SNCA, Synuclein Alpha; SOD, superoxide dismutase; TAZ, transcriptional coactivator with PDZ-binding motif; TM9SF1, transmembrane 9 superfamily member 1; TNF-α, tumor necrosis factor-alpha; UCP, uncoupling protein. ↑, increase; ↓, decrease; ↔, no change. Figure 1 illustrates the potential effects of GTCs on skeletal muscle. GTCs have been shown to effectively suppress inflammation and oxidative stress and promote autophagic and mitophagy activities. Improving the quality of mitochondria (decreased ROS leakage and improved oxidative metabolism) and potentially increasing mitochondrial biogenesis could provide machinery for muscle cell growth and regeneration capacity. Although these potential benefits of GTCs on skeletal muscle health need to be further elucidated, GTCs are promising dietary nutritional supplements capable of maintaining muscle homeostasis and combating disuse muscle atrophy with aging.

Potential Side Effects of Green Tea
Although existing evidence supports the beneficial effect of green tea on joint and muscle health, there are potential side effects associated with green tea intake. Since EGCG in GTP can bind with iron, excessive green tea drinking can lead to iron deficiency anemia [39,146]. Caffeine in green tea may interfere with some medications. The most serious caffeine-related central nervous system

Potential Side Effects of Green Tea
Although existing evidence supports the beneficial effect of green tea on joint and muscle health, there are potential side effects associated with green tea intake. Since EGCG in GTP can bind with iron, excessive green tea drinking can lead to iron deficiency anemia [39,146]. Caffeine in green tea may interfere with some medications. The most serious caffeine-related central nervous system effects are seizure and delirium, followed by cardiovascular side effects such as tachycardia and cardiac arrhythmia. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine and many clinical drugs including antiarrhythmics (mexiletine), some selective serotonin reuptake inhibitors (particularly fluvoxamine), antipsychotics (clozapine), bronchodilators (furafylline and theophylline), and quinolones (Ciprofloxacin) [147]. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and the aforementioned drugs [148]. Green tea caffeine also inhibited the metabolism of clozapine, an antipsychotic drug, leading to clozapine toxicity [149]. Vitamin K in green tea inhibits the effects of warfarin, an anticoagulant [150]. Too much GTP may cause hypokalemia leading to muscle weakness [151]. Excessive green tea caffeine may impair thyroid function [152]. Caffeine in green tea is a nervous system stimulant. Consuming more than 300 mg of caffeine per day may reduce sleep quality and cause insomnia, irritability, depression, anger, and anxiety [153].
Too much green tea may cause heartburn, which is a typical symptom of gastroesophageal reflux disease [154]. The diuretic effect of caffeine affects bladder function by increasing neuronal activation of the micturition center [155]. Lastly, green tea may stain teeth [156].

Conclusions, Limitations, and Future Directions of Research
Both OA and SC are closely related to aging and are prevalent in the elderly population. This review summarizes the state of the knowledge about possible pharmacological mechanisms of green tea and EGCG in terms of mitigation of OA progression via its anti-inflammatory, antioxidative stress, and antioxidant properties in preclinical and clinical studies. GTCs and EGCG have been shown to (i) downregulate inflammatory mediators, COX-2, IL-1β, TNF-α, MMPs, iNOS, and ADMTS5, by suppressing NF-κB and MAPK pathways, (ii) upregulate anabolic mediators, TGF-β1, TGF-β2, and its receptors TGF-βR1 and TGF-βRII, and (iii) modulate miRNAs expression, resulting in reduced chondrocyte death, collagen degradation, and cartilage erosion. GTCs including EGCG have great potential as a novel approach in mitigating the progression of OA and SC (Figure 1).
There are some limitations to this review. Overall, this review is based on limited studies investigating the effects of GTCs on OA and SC during aging. Green tea contains different types of catechins, the composition of which varies with planting environments and seasons. Such a variation in ingredients of GTCs and the interaction among them may result in different benefits to joint and skeletal muscle health, although this limitation does not apply to a number of studies covered in this review using pure monomers of catechins such as EGCG. The translation of results from animal studies to humans requires the investigation of the bioavailability, safety, and efficacy of green tea and EGCG in OA or SC patients. As most clinical studies on GTCs' effects on OA and SC are not randomized controlled clinical trials, current limited human studies do not provide evidence at a sufficiently high level to confirm GTCs' beneficial effects on joint and skeletal muscle health in OA and SC patients. Optimal treatment, dosage, and time of GTCs' intervention for the maintenance or promotion of joint and skeletal muscle health are important but not well studied yet. Quite a few studies covered in the present review included exercise intervention in addition to green tea supplement. Good lifestyles such as exercise may also improve joint and skeletal muscle health. However, there is limited knowledge on the interaction between different lifestyle factors and green tea supplements and how they benefit OA and SC patients.
For patients with concomitant OA and SC, the disorders may interact and complicate clinical progression. In this review, we found a common pathomechanism for both disorders. Therefore, a common therapeutic strategy can be employed for the management of the common denominators for both OA and SC, i.e., inflammation, excessive oxidative stress, mitochondrial dysfunction, and impairment of autophagy activity. Such a treatment may need to start early in life and last a lifetime, considering the progression of the disorders with the continuous and irreversible aging process. GTCs have been demonstrated as potential functional products to prevent, delay, alleviate, and even treat joint-and skeletal-muscle-related disorders related to aging. EGCG may be adjunctively administered with OA or SC drugs to reduce the drug dose and interval between episodes by additively or synergistically enhancing anti-OA and anti-SC efficacies. Well-designed prospective human clinical trials and translational studies to test pharmacological and nonpharmacological therapies are warranted to evaluate their effects on OA and SC in terms of biochemical outcomes, alleviation of symptomatic pain and muscle mass reduction, and improvement of physical function, especially in patients with concomitant OA and SC.
Gut microbiota in the gastrointestinal tract has been identified as a possible factor causing age-related cartilage and skeletal muscle disorders. Emerging evidence suggests that the gut microbiome plays an important role in joint health by modulating nutrient absorption, intestinal permeability, metabolic immunity, cartilage-gut microbiome axis, and excretion of functional metabolites [157][158][159][160]. The mechanisms concerning how intestinal microbiota composition and metabolites affect OA and SC pathogenesis remain unclear [161][162][163][164]. Studies have reported that long-term treatment with green tea polyphenols modified the gut-microbiota-dependent metabolism of energy, bile constituents, and micronutrients in female Sprague-Dawley rats [165,166]. Future research should investigate the potential impacts of green tea and EGCG on the gut microbiota composition and functionality along with joint parameters such as chondrocyte metabolism, cartilage integrity, and pain reduction in OA animals. Such studies can provide new knowledge on the effects of green tea and EGCG on joint health in terms of the modification of the gut microbiota. A similar approach can be taken to investigate the effects of green tea and EGCG on the gut microbiota composition and functionality and how they in turn affect skeletal muscle parameters, such as myocyte metabolism, skeletal muscle size, composition, and function in animals with SC.