Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise
Abstract
:1. Introduction
2. Nrf2 Activation and Transcription
3. Nrf2, the Antioxidant Response Master Regulator
4. Physical Exercise and Redox Response
4.1. Oxidative Stress and Exercise
4.2. Signaling Pathways and the Epigenetic Changes Induced by ROS during Physical Exercise
4.3. Adaptative Responses According to the Exercise Training Modality
5. Regulation of Nrf2 by Physical Training
5.1. Nrf2 in Aerobic Exercise Models
5.2. Nfr2 in Resistance Exercise Models
5.3. Physical Exercise and Bioactivador Compounds of Nrf2
6. Nrf2 and Modulation of Energy Metabolism during Exercise
7. Clinical Implications of Therole of Nrf2 in Physical Exercise
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Pathway/Enzimatic System | Activity |
---|---|
Glutathione synthesis and regeneration: | |
-GCL: GCLM/GCLC complex | Carrying out glutathione synthesis forms glutamate and cysteine |
-GPx | Detoxification of H2O2 |
-GR | Reduction of GSSG to GSH |
-XCT | Transports cysteine to the cell to be reduced to cysteine from GSH |
Phase-II detoxifying enzymes: | |
-HO-1 | Degradation of the heme group gives rise to biliverdin, free iron, and carbon monoxide |
-UGT | Glucoronidation: conjugation of glucuronic acid |
-SULT | Sulfonation: the addition of sulfuryl groups donated by 3′-PhosphoAdenosine-5′-PhosphoSulfate (PAPS) to hydroxyl or amine groups |
Expression of NADPH- producing enzymes: | |
-G6PD | Synthesis of NADPH in the PPP pathwa |
-IDH | Synthesis of NADPH in the conversion ofisocytrate into α-ketoglutarate in the KC |
-ME1 | Synthesis of NADHP in the conversion of pyruvate into malate in the KC |
Expression of Thioredoxins: | |
-TXN1 | Their two active cysteine residues can be oxidized for reducing the oxidized thiols of proteins |
-TXNRD1 | NADPH-dependent can reduce oxidized TXN |
Detoxification of quinones: | |
-NQO1 | These compete with the CYP 450 reductases and convert quinones into more stable molecules (quinoles) |
-AKR | |
GCL: glutamate-cysteine ligase | SULT´s: sulfotransferases |
GCLM: glutamate-cysteine ligase modifier subunit | G6PD: glucose-6-phosphate dehydrogenase |
GCLC: glutamate-cysteine ligase catalytic subunit | PPP: pentose phosphate pathway |
GST: glutathione S-transferases | NADPH: nicotinamine dinucleotide phophate |
GR: glutathione reductase | IDH: isocitrate dehydrogenase |
XCT: cystine/glutamate transporter | ME1: malic enzyme 1 |
GSSG: oxidized glutathione | KC: Kreb’s cycle |
GSH: reducedglutathione | TXN1: thioredoxine 1 |
GPx: glutathioneperoxidases | TXNRD1: thioredoxine reductase 1 |
HO-1: heme oxygenase-1 | NQO1: N-quinone oxido reductase 1 |
UGT: UDP-glucuronosyltransferases | AKR: aldo-ketoreductase |
KC: Kreb’s cycle |
Model | Training Protocol | Objective | Results | Reference |
---|---|---|---|---|
Male mice Nrf2, WT, and KO aged 3 and 12 months | Free run on wheel for 6–8 weeks. Estimation of revolutions in 24 h and converted into distance (km) | Estimate the role of Nrf2 in biogenesis and mitochondrial content of SkM and the physical performance | Without difference in mitochondrial content ↓mitochondrial respiration, in KO mice: ↑ROS IMF ↓performance, ↑ fatigue. In WT ↑ COX. ET normalized ROS, performance, and respiration in KO | Crilly et al. [117] |
Male mice 13 weeks of age Nrf2+/+ and Nrf2−/− | AT (5–10 m/min) 3 days prior to administration with SFN ExT on treadmill 5 m/min up to 28 m/min increase every 3 min | Evaluate performance, markers of damage, and OS ExT low conditions of ExT in mice administered SFN pre-treatment | ↑distance covered by Nrf2+/+ SFN, ↓ markers of damage in Nrf2+/+ SFN after the SFN test → protection against muscle damage, regulation of Nrf2, and the antioxidant response. ↓ fatigue due to ↓of OS causing ExT | Oh et al. [118] |
Young males aged 25 ± 1 years | HIIT Cycling protocol of 30 min Sample taking of blood before and after the session | Determine whether HIIT exercise can more efficiently evaluate Nrf2 than MET in humans | ↑ Nrf2 in HIIT vs. MET ↑ GR activity and response ↑ 8-isoprostanes | Done et al. [119] |
Male Sprague–Dawley rats aged 20–22 weeks | Exhaustive swimming every day for 3 weeks. After each session, the animals received 20–75 mg of LN or 100 mg of AA | Determine the effect of supplementation with LN on the diminution of fatigue and the modulation of the Nrf2/ARE pathway in a forced swimming model in rats | LN ↑performance resistance exercise normalized metabolic markers. ↓LA and LDH ↑capacity of resistance to the exercise ↑activity of antioxidant enzymes and antioxidant capacity ↓ TNFα, IL-1β, and IL-6 ↑ IL-10 anti-inflammatory in SkM and in liver | Duan et al. [120] |
Male aged mice ICR/CD-1 | AE at different durations (45, 90, 120, or 150 min) | Evaluate effect of AE on the Ref1/Nrf2 pathway, association with H2O2 and EAS | AE ↑ OS by the Ref1/Nrf2 pathway in time-dependent fashion in linear correlation of the content of H2O2 and the expression of Ref1/Nrf2. ↑GSH and ↑ activity of MnSOD. CuZnSOD not modified | Wang et al. [121] |
Male mice C57/BL6/SJ aged 15–30 weeks Nrf2+/+ and Nrf2−/− | AT 5 days prior to the study, 5 min (0–9 m/min) 0 degrees of inclination ET included 30–60 min of treadmill running at 10–15 m min−1 at 10% inclination, 4–5 days per week. AE consisted of 1 h of treadmill running at 12 m min, at a 10° inclination | Determine the role of NFE2L2 in AE mitochondrial biogenesis and antioxidant response | ROS and NO regulate the expression of NFE2L2 in SkM cells ↓ NFE2L2 →↓ tolerance to exercise, mitochondrial density, and low SOD activity ↓of markers of mitochondrial biogenesis, citrate synthase, and mtDNA AE, NO, and H2O2→increase of NRF-1 and mtTFA was dependent on NFE2L2 | Merry et al. [122] |
Male mice aged 20 months Nrf2+/+ and Nrf2−/− | Test of previous resistance ability; 1 week of treadmill running for 10 min; 15–22 m/min; 0–12% inclination. HIES treadmill running for 6 weeks at 20–25 m/min; 12% inclination for 60 min per day | Determine the role of Nrf2 under stress by HIES in atrial cardiomyocyte hypertrophic changes | HIES →↑ markers of the gene expression of hypertrophy of cardiomyocytes (Anf, Bnf, and β-Mhc) in mice Nrf2−/− ↓Gclc, Gsr, and Gstμ, levels of protein of NQO1, Cat, GPX1, GSH in Nrf2−/− after HIES ↑expression of LC3 and ATG7 ↑ ubiquitination of ATG7 →↑ OS | Kumar et al. [123] |
Male Wistar rats aged 8 weeks | 1 week of adaptation CE: 25 m/min, 45 min/day, 5 days per week during 6 weeks Supplementation of Coenzyme Q10 at doses of 300 mg/kg | Investigate the effect of Coenzyme Q10 or ubiquinone on NFκB, IκB, Nrf2, and HO-1 after CET after 6 weeks of training in sedentary and active rats. | ↓Significant NFκB in muscle, liver, and heart in the group that received Q10 post-training vs. sedentary group. ↑ Nrf2 and HO-1 in muscle, liver, and heart of the active group. ↓plasma triglycerides Without changes in metabolites related with CHO and proteins | Pala et al. [124] |
Male mice Nrf2+/+ and Nrf2−/− aged 2 months | AE on treadmill; 60 min/day, 14 m/min, 10% inclination, for 2 days. | Determine the impact of the AE in the activation of the Nrf2/ARE pathway and of the EAS system in mouse heart | ↑activation of the Ref1/Nrf2 pathway and of the EAS pathway in mice Nrf2+/+. ↑ OS and ↓ EAS (Cat, NQO1, GCS, GSR, GPx-1, G6PD, GSH) in Nrf2−/− ↑activation of the Ref1/Nrf2 pathway and of the EAS pathway in Nrf2+/+ in old mice vs. Nrf2 AE protects against OS in cardiac muscle in mice | Muthusamy et al. [125] |
Male mice C57/Bl6/SJ Young (aged ~2 months) and old (aged ≥23 months) Nrf2+/+ and Nrf2−/− | EES: 2 consecutive days on treadmill 90 min/day; 20 m/min; 12% inclination MET: 50 min/day; 10 m/min; 7% inclination min/day for 6 weeks. The protocol included 5 min of ramping at 5 m/min, the speed Increased to 10 m/min/45 min | Evaluate the regulation of Nrf2 depending on age, the antioxidant mechanisms, and redox equilibrium in mouse cardiac muscle Antioxidants under EES and MET conditions | ↑susceptibility in old mice by OS produced by EES Proteins of the ARE antioxidant system ↑ in young mice, with respect to the old mice. ↓ Cat, NQO1 young mice Nrf2−/−, in old mice ↓G6PD, NQO1, cat, HO-1, and GPX1 MET: ↑Nrf2 nuclear and EAS in heart of old mice close to the levels of the young mice | Gounder et al. [34] |
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Vargas-Mendoza, N.; Morales-González, Á.; Madrigal-Santillán, E.O.; Madrigal-Bujaidar, E.; Álvarez-González, I.; García-Melo, L.F.; Anguiano-Robledo, L.; Fregoso-Aguilar, T.; Morales-Gonzalez, J.A. Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise. Antioxidants 2019, 8, 196. https://doi.org/10.3390/antiox8060196
Vargas-Mendoza N, Morales-González Á, Madrigal-Santillán EO, Madrigal-Bujaidar E, Álvarez-González I, García-Melo LF, Anguiano-Robledo L, Fregoso-Aguilar T, Morales-Gonzalez JA. Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise. Antioxidants. 2019; 8(6):196. https://doi.org/10.3390/antiox8060196
Chicago/Turabian StyleVargas-Mendoza, Nancy, Ángel Morales-González, Eduardo Osiris Madrigal-Santillán, Eduardo Madrigal-Bujaidar, Isela Álvarez-González, Luis Fernando García-Melo, Liliana Anguiano-Robledo, Tomás Fregoso-Aguilar, and José A. Morales-Gonzalez. 2019. "Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise" Antioxidants 8, no. 6: 196. https://doi.org/10.3390/antiox8060196