What is Epicatechin?
Epi is one of the few polyphenols whose effect on SkM has been studied in three key respects: 1) oxidative stress, 2) inflammatory pathways, 3) muscular structure and function.
Contents of a study are writtein down below for you to better understand the aspects in which epicatechin helps you.
EPI AND OXIDATIVE STRESS IN SKM
Epi may affect several pathways, including Nrf2 and NF-kB, to reduce cellular oxidative stress and limit DNA damage. For one, Epi can modulate NOX, NOS, and consequently oxidative stress and NO bioa- vailability. On the other hand, Epi is a known Nr- f2 pathway activator involved in oxidative stress regu- lation. Under normal, unstressed conditions, Nrf2 inter- acts with the cytosolic Keap1, which targets Nrf2 for proteasomal degradation. However, increased ROS and NO levels lead to Keap1 oxidation. This re- leases Nrf2 and permits its nuclear translocation where it heterodimerizes with musculoaponeurotic fibrosarco- ma (Maf) proteins to activate antioxidant and detoxifi- cation enzyme gene transcription. In liver cells, the activation and nuclear translocation of Nrf2 are al- so induced by AMPK. AMPK acts as an energy sensor in SkM and is activated by increased AMP levels. Nr- f2’s nuclear import can also be inhibited by glycogen synthase kinase 3 beta (GSK-3β), which in turn is in- hibited by the serine/threonine-protein kinases (Akt)/- mammalian target of rapamycin (mTOR) pathway that is regulated by growth factors and nutrient availability.
Interestingly, Epi modifies the activity of all these pathways: it increases NO levels, activates AMPK, and inhibits GSK-3β, to promote Nrf2’s nuclear transloca- tion and ultimately increase antioxidant and detoxifica- tion enzyme levels. In an interesting study, healthy, se- dentary subjects consumed 20 g of dark chocolate (a good source of Epi) daily for three months. This re- duced oxidative stress and protein carbonylation levels as well as markedly increased reduced glutathione lev- els in SkM. The same group supplemented dia- betes and heart failure patients for three months with Epi-rich cocoa (100 mg/day). The authors reported this to have re-established glutathione levels and decreased nitrotyrosilation and carbonylation levels, as well as in- creased SOD2 and CAT protein expression and activi- ty levels. They found that the principal perturbations in oxidative stress in SkM in this vulnerable population can be reversed by three months of Epi supplementation. Future studies are required to elucidate the exact mechanisms through which Epi mediates its an- tioxidant effect and/or affect detoxification enzymes in SkM.
EPI AND INFLAMMATION IN SKM
The inflammatory processes occurring in SkM have been associated with various disorders, including in- sulin resistance, sarcopenia, and even muscle diseases. Epi can inhibit intracellular inflammatory signalling in several ways, one being by inhibiting the Toll-Like Re-
ceptors 2 (TLR2) and 4 (TLR4) signalling pathways. TLR2 and TRL4 are transmembrane recep- tors that play a role in the innate immune system and are found in various tissues, including skeletal muscle, the liver, and lungs. The recruitment of Myeloid differ- entiation primary response 88 (MyD88) or TIR-do- main-containing adapter-inducing interferon-β (TRIF) to an intracellular TLR domain initiates inflammatory signalling [85] by triggering several phosphorylation cascades that activate key proteins, including tumor growth factor-β activated kinase (TAK) and IKK. Th- ese, in turn, increase pro-inflammatory cytokine levels, such as IL-6 and TNF-α, via NF-κB, the so-called “master regulator” of inflammation. Moreover, once ac- tivated, TAK activates the p38 MAPK, JNK, and ERK1/2-(MAPK) pathways [86]. MAPK signalling is involved in SkM inflammation, mitochondrial biogene- sis, and remodeling.
In several cellular models, Epi attenuated NF-kB pathway inflammatory by downregulating TLR2 and TLR4 signalling. Future studies are need- ed to investigate the relationship between Epi consump- tion and TLR signaling in SkM. TLR2 and TLR4 have also been implicated in inflammation and insulin in human SkM cells. The obese, the elderly, and muscle disease patients often suffer from a chronic low-grade inflammatory state and experience a high de- gree of muscle wasting. Pro-inflammatory cytokines, interleukins (IL-1β, IL-3, 5, 6 and 15), cyclooxygenase 2, TNF-α, NF-kB, and interferon γ were significantly decreased with Epi treatment (1 mg/Kg/day for 4 week- s) using a mouse model system of aging. Treating C2C12 mouse SkM cells with 0.75 mM palmitate for five hours renders them insulin resistant by down-regu- lating the insulin signaling pathway activity. This was reversed by a 3-hour ECG treatment of the cells, which attenuated insulin receptor substrate-1 (IRS-1) serine 307 (Ser307) phosphorylation and activated Akt, ERK, p38 MAPK, and AMPK signalling.
Inflammatory signalling pathways are closely linked to oxidative stress. For instance, chronically in- creased ERK signaling increases oxidative stress, re- sulting in the expression of atrogenes that induce mus- cle atrophy. As such, glucocorticoid-treated C2C12 cells have increased atrogene expression, which is sup- pressed by Epi treatment through the inhibition of ERK signaling.
Acute MAPK activation underlies many beneficial SkM adaptations. As such, a ~250-fold increased p38 MAPK SkM phosphorylation state was observed in rats injected with 1.0 mg/Kg bw of Epi for 30 days. Likewise, PGC-1α levels were increased, which stimulated mitochondrial respiratory kinetics. These effects were maintained for 15 days after the end of Epi treatment. The current evidence from in vitro studies suggests that Epi supplementation could positively af- fect the activation or normalize the different MAPK phosphorylation states. Future studies should confirm these important findings in human SkM.
EFFECTS OF EPI ON SKM STRUCTURE AND FUNCTION
Epi interacts with and activates the G-protein cou- pled estrogen receptor (GPER) to stimulate mitochondrial biogenesis and cell growth in C2C12 SkM cells. Downregulating GPER using siRNA -partially re- duced mitochondrial biogenesis and completely blocked cell size upon Epi treatment, possibly indicat- ing the involvement of another, albeit unknown, recep- tor.
SkM myostatin and β-galactosidase levels increase with aging whilst follistatin, and myogenic regulatory factor 5 (Myf5) levels decrease. In mice, Epi (1 mg/Kg bw for two weeks) decreased myostatin and β-galac- tosidase levels but increased follistatin levels. In hu- mans, a seven-day treatment with 25 mg of pure Epi in- creased the plasma follistatin/myostatin ratio in both young and old subjects.
As mentioned in the first part of this review, good mitochondrial function is essential for adequate muscle structure and function. DAPC integrity is key to the maintenance of SkM structure and function [96]. In a pilot study, Taub et al. (2013) showed that type 2 dia- betics and heart failure patients who received 100 mg/- day of Epi for 3 months increased DAPC protein lev- els, such as dystrophin, utrophin, dysferlin, and α-β-γ- δ-sarcoglycan. Furthermore, they observed that Epi supplementation decreased myostatin levels and in- creased levels of follistatin and myogenic factors such as myocyte enhancer 2A (MEF2A), Myf5, myogenic differentiation (MyoD), and myogenin (MyoG).
The reduced regenerative capacity of SkM stem and satellite cells may induce sarcopenia and strength loss [98]. C2C12 mouse muscle cells treated with ECG had increased myotubal MyoD, MyoG, and myosin heavy chain (MyHC) transcriptional levels after differ- entiation, indicative of enhanced skeletal muscle regen- eration and repair. This suggests that Epi activates p38 MAPK, increasing MyoD levels and myogenic protein production.
Mitochondrial biogenesis is essential to energetical- ly support SkM growth, differentiation, and function. In C2C12 myotubes, Epi (25 and 50 μM) significantly
increased mitochondrial DNA gene expression, includ- ing cytochrome b and cytochrome c oxidase subunit II, and mitochondrial enzyme activity, including citrate synthase and cytochrome c oxidase [96]. This demons- trates the great potential of Epi as a novel mitochon- drial-activating agent in SkM. Recently, Dugar et al. (2020) demonstrated that in bovine coronary artery en- dothelial cells, Epi increased ATP and electron trans- port chain complexes II-IV levels, concluding that like the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR), Epi stimulates mitochondrial biogenesis.
EPI AND SKM DISEASES
Despite robust scientific evidence on the positive ef- fects of Epi supplementation on SkM structure and function, as well as on mitochondrial function, few studies have explored the possible therapeutic applica- tion of Epi in skeletal muscle diseases. Muscle diseas- es such as dystrophies are disorders characterized by a loss of muscle mass and function accompanied by in- creased oxidative stress and mitochondrial dysfunc- tion. In an interesting and promising study, dystrophic, δ-sarcoglycan null mice were treated with Epi (1 mg/Kg, twice daily) for two weeks. The mice nor- malised their total protein carbonylation, recovered their glutathione/oxidized glutathione ratio, and en- hanced superoxide dismutase 2, catalase, and citrate synthase activity, indicative of reduced oxidative stress. In addition, Epi treatment decreased fibrosis and improved muscle function in animals with muscular dystrophy [102]. The same group of researchers recent- ly published the first article on Epi treatment of pa- tients with Becker's disease [103]. Becker's disease is a dystrophinopathy characterized by mitochondrial dys- function leading to increased ROS and inflammation levels and decreased satellite cell activation, which ulti- mately affects muscle structure and function. Becker's muscle disease patients orally received 50 mg Epi twice daily (total dose: 100 mg/day) for eight weeks. Biological and functional outcomes were assessed be- fore and after treatment. AMPK, PGC-1α, mitofilin (mitochondrial cristae-associated protein), and LKB1 (an upstream activator of AMPK signaling) proteins were increased in the SkM of Becker’s patients after treatment.
Furthermore, levels of the structural contractile pro- teins myosin and actin α1 were significantly increased, as were levels of SkM growth regulators such as follis- tatin, whilst myostatin levels were reduced. In addi- tion, SkM regeneration-related proteins as well as Myf5, MyoD, myogenin, and MEF2A were increased by Epi supplementation. Similar effects were found for dysferlin and utrophilin protein levels, which are in- volved in SkM structural maintenance. These biologi- cal changes in the SkM were accompanied by function- al muscle improvements. In addition, patients im- proved cardio-respiratory (heart rate and oxygen con- sumption [VO2]) and metabolic (lactate) parameters. This suggests Epi supplementation may be a viable therapeutic approach for Becker's disease patients and, to an extent, other muscular dystrophy patients, too [103]. Although there are no studies on the potential cellular effect of Epi in the regulation of endoplasmic reticulum (ER) stress [104], recent studies showed that the EGCG interferes with protein processing in the ER, presumably by inhibiting glucosidase II in mouse hepa- toma cells [105]. Interestingly, ER stress in the SkM has been hypothesized to play a role in sarcopenia and myopathies.
CONCLUSION
In SkM, Epi may interact with and activate the GPER signaling cascade to reduce inflammation, oxida- tive stress, and loss of SkM quality by 1) inhibiting the TLR pathway; 2) stimulating muscle anabolism via Ak- t/mTOR, which also relieves the Keap1-mediated inhi- bition of Nrf2 to increase antioxidant and detoxifica- tion enzyme levels; 3) activating AMPK leading to Nr- f2’s nuclear translocation, and increased PGC-1α lev- els, thereby increasing mitochondrial biogenesis; 4) in- creasing NO and NOX levels which also trigger Nrf2’s nuclear translocation. Increased levels of antioxidant components and detoxification enzymes as well as mi- tochondrial biogenesis increase and/or activate key pro- teins in the muscle, leading to improved SkM function- ality and quality. The dotted arrow in (Fig. 3) denotes that there may be another SkM receptor able to interact with epicatechin.
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