Exercise-induced oxidative stress: Friend or foe?

Scott K Powers, Rafael Deminice, Mustafa Ozdemir, Toshinori Yoshihara, Matthew P Bomkamp, Hayden Hyatt, Scott K Powers, Rafael Deminice, Mustafa Ozdemir, Toshinori Yoshihara, Matthew P Bomkamp, Hayden Hyatt

Abstract

The first report demonstrating that prolonged endurance exercise promotes oxidative stress in humans was published more than 4 decades ago. Since this discovery, many ensuing investigations have corroborated the fact that muscular exercise increases the production of reactive oxygen species (ROS) and results in oxidative stress in numerous tissues including blood and skeletal muscles. Although several tissues may contribute to exercise-induced ROS production, it is predicted that muscular contractions stimulate ROS production in active muscle fibers and that skeletal muscle is a primary source of ROS production during exercise. This contraction-induced ROS generation is associated with (1) oxidant damage in several tissues (e.g., increased protein oxidation and lipid peroxidation), (2) accelerated muscle fatigue, and (3) activation of biochemical signaling pathways that contribute to exercise-induced adaptation in the contracting muscle fibers. While our understanding of exercise and oxidative stress has advanced rapidly during the last decades, questions remain about whether exercise-induced increases in ROS production are beneficial or harmful to health. This review addresses this issue by discussing the site(s) of oxidant production during exercise and detailing the health consequences of exercise-induced ROS production.

Keywords: Hormesis; Oxidants; Radicals; Reactive oxygen species; Skeletal muscle.

Copyright © 2020. Production and hosting by Elsevier B.V.

Figures

Fig. 1
Fig. 1
Potential sites of the production or reactive oxygen species in contracting skeletal muscles. CAT = catalase; GPX = glutathione peroxidase; H2O2 = hydrogen peroxide; NOX = NADPH oxidase; O2.− = superoxide; ·OH = hydroxyl radical; PLA2 = phospholipase A2; SOD = superoxide dismutase. Modified from Powers and Jackson.
Fig. 2
Fig. 2
Relationship between cellular redox state and skeletal muscle force production. Note that maximal force production in skeletal muscle requires an optimal redox state. Movement away from the optimal redox state (i.e., an increase in reduction or oxidation) results in a decrease in maximal isometric force production. ROS = reactive oxygen species. Modified from Reid
Fig. 3
Fig. 3
(A) Relationship between cellular levels of ROS and physiological function. This biphasic bell-shaped curve represents the ROS hormesis curve. (B) Relationship between the exercise-induced muscle fiber levels of reactive oxygen species and physiological function. This figure predicts that training-induced increases in muscle fiber levels of ROS does not reach a detrimental level because of exercise-induced fatigue. ROS = reactive oxygen species.

References

    1. Kruk J., Aboul-Enein H.Y., Kladna A., Bowser J.E. Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis. Free Radic Res. 2019;53:497–521.
    1. Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757–772.
    1. Valko M., Rhodes C.J., Moncol J., Izakovic M., Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160:1–40.
    1. Wei W., Liu Q., Tan Y., Liu L., Li X., Cai L. Oxidative stress, diabetes, and diabetic complications. Hemoglobin. 2009;33:370–377.
    1. Powers S.K., Jackson M.J. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev. 2008;88:1243–1276.
    1. Kraus W.E., Powell K.E., Haskell W.L., Janz K.F., Campbell W.W., Jakicic J.M. Physical activity, all-cause and cardiovascular mortality, and cardiovascular disease. Med Sci Sports Exerc. 2019;51:1270–1281.
    1. Sies H. Academic Press; London: 1985. Oxidative stress.
    1. Jones D.P. Redefining oxidative stress. Antioxid Redox Signal. 2006;8:1865–1879.
    1. Commoner B., Townsend J., Pake G.E. Free radicals in biological materials. Nature. 1954;174:689–691.
    1. Halliwell B., Gutteridge J. 4th ed. Oxford Press; Oxford: 2007. Free radicals in biology and medicine.
    1. Hensley K., Floyd R.A. Reactive oxygen species and protein oxidation in aging: a look back, a look ahead. Arch Biochem Biophy. 2002;397:377–383.
    1. Kobzik L., Reid M.B., Bredt D.S., Stamler J.S. Nitric oxide in skeletal muscle. Nature. 1994;372:546–548.
    1. Balke J.E., Zhang L., Percival J.M. Neuronal nitric oxide synthase (nNOS) splice variant function: insights into nitric oxide signaling from skeletal muscle. Nitric Oxide. 2019;82:35–47.
    1. Adams V., Nehrhoff B., Späte U., Linke A., Schulze P.C., Baur A. Induction of iNOS expression in skeletal muscle by IL-1beta and NFkappa B activation: an in vitro and in vivo study. Cardiovasc Res. 2002;54:95–104.
    1. Förstermann U., Sessa W.C. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33 829–37a-d.
    1. Reid M.B. Redox interventions to increase exercise performance. J Physiol. 2016;594:5125–5133.
    1. Ji L.L., Kang C., Zhang Y. Exercise-induced hormesis and skeletal muscle health. Free Radic Biol Med. 2016;98:113–122.
    1. Culotta V.C., Yang M., O'Halloran T.V. Activation of superoxide dismutases: putting the metal to the pedal. Biochim Biophys Acta. 2006;1763:747–758.
    1. Suzuki K., Ohno H., Oh-ishi S., Kizaki T., Ookawara T., Fukii J. Superoxide dismutases in exercise and disease. In: Sen C.K., Packer L., Hänninen O., editors. Handbook of oxidants and antioxidants and exercise. Elsevier Science; Amsterdam: 2000. pp. 243–295.
    1. Hearn A.S., Tu C., Nick H.S., Silverman D.N. Characterization of the product-inhibited complex in catalysis by human manganese superoxide dismutase. J Biol Chem. 1999;274:24457–24460.
    1. Brigelius-Flohé R. Glutathione peroxidases and redox-regulated transcription factors. Biol Chem. 2006;38710:1329–1335.
    1. Björnstedt M., Kumar S., Björkhem L., Spyrou G., Holmgren A. Selenium and the thioredoxin and glutaredoxin systems. Biomed Environ Sci. 1997;10:271–279.
    1. Balsera M., Buchanan B.B. Evolution of the thioredoxin system as a step enabling adaptation to oxidative stress. Free Radic Biol Med. 2019;140:28–35.
    1. Arnér E.S., Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000;267:6102–6109.
    1. Rhee S.G., Kil I.S. Multiple functions and regulation of mammalian peroxiredoxins. Annu Rev Biochem. 2017;86:749–775.
    1. Wadley A.J., Aldred S., Coles S.J. An unexplored role for peroxiredoxin in exercise-induced redox signalling. Redox Biol. 2016;8:51–58.
    1. Dillard C.J., Litov R.E., Savin W.M., Dumelin E.E., Tappel A.L. Effects of exercise, vitamin E, and ozone on pulmonary function and lipid peroxidation. J Appl Physiol. 1978;45:927–932.
    1. Davies K.J., Quintanilha A.T., Brooks G.A., Packer L. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun. 1982;107:1198–1205.
    1. Jackson M.J., Edwards R.H., Symons M.C. Electron spin resonance studies of intact mammalian skeletal muscle. Biochim Biophys Acta. 1985;847:185–190.
    1. Jackson M.J. Control of reactive oxygen species production in contracting skeletal muscle. Antioxid Redox Signal. 2011;15:2477–2486.
    1. Bloomer R.J., Goldfarb A.H. Anaerobic exercise and oxidative stress: a review. Can J Appl Physiol. 2004;29:245–263.
    1. Groussard C., Rannou-Bekono F., Machefer G., Chevanne M., Vincent S., Sergent O. Changes in blood lipid peroxidation markers and antioxidants after a single sprint anaerobic exercise. Eur J Appl Physiol. 2003;89:14–20.
    1. McBride J.M., Kraemer W.J., Triplett-McBride T., Sebastianelli W. Effect of resistance exercise on free radical production. Med Sci Sports Exerc. 1998;30:67–72.
    1. Scheffer D.L., Silva L.A., Tromm C.B., da Rosa G.L., Silveira P.C., de Souza C.T. Impact of different resistance training protocols on muscular oxidative stress parameters. Appl Physiol Nutr Metab. 2012;37:1239–1246.
    1. Novelli G.P., Bracciotti G., Falsini S. Spin-trappers and vitamin E prolong endurance to muscle fatigue in mice. Free Radic Biol Med. 1990;8:9–13.
    1. Shindoh C., DiMarco A., Thomas A., Manubay P., Supinski G. Effect of N-acetylcysteine on diaphragm fatigue. J Appl Physiol (1985) 1990;68:2107–2113.
    1. Reid M.B. Free radicals and muscle fatigue: of ROS, canaries, and the IOC. Free Radic Biol Med. 2008;44:169–179.
    1. Criswell D., Powers S., Dodd S., Lawler J., Edwards W., Renshler K. High intensity training-induced changes in skeletal muscle antioxidant enzyme activity. Med Sci Sports Exerc. 1993;25:1135–1140.
    1. Ji L.L., Fu R., Mitchell E.W. Glutathione and antioxidant enzymes in skeletal muscle: effects of fiber type and exercise intensity. J Appl Physiol. 1992;73:1854–1859.
    1. Ji L.L., Stratman F.W., Lardy H.A. Antioxidant enzyme systems in rat liver and skeletal muscle. Influences of selenium deficiency, chronic training, and acute exercise. Arch Biochem Biophys. 1988;263:150–160.
    1. Laughlin M.H., Simpson T., Sexton W.L., Brown O.R., Smith J.K., Korthuis R.J. Skeletal muscle oxidative capacity, antioxidant enzymes, and exercise training. J Appl Physiol. 1990;68:2337–2343.
    1. Leeuwenburgh C., Fiebig R., Chandwaney R., Ji L.L. Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems. Am J Physiol. 1994;267:R439–R445.
    1. Leeuwenburgh C., Hollander J., Leichtweis S., Griffiths M., Gore M., Ji L.L. Adaptations of glutathione antioxidant system to endurance training are tissue and muscle fiber specific. Am J Physiol. 1997;272:R363–R369.
    1. Powers S.K., Criswell D., Lawler J., Ji L.L., Martin D., Herb R.A. Influence of exercise and fiber type on antioxidant enzyme activity in rat skeletal muscle. Am J Physiol. 1994;266:R375–R380.
    1. Powers S.K., Criswell D., Lawler J., Martin D., Ji L.L., Herb R.A. Regional training-induced alterations in diaphragmatic oxidative and antioxidant enzymes. Respir Physiol. 1994;95:227–237.
    1. Powers S.K., Criswell D., Lawler J., Martin D., Lieu F.K., Ji L.L. Rigorous exercise training increases superoxide dismutase activity in ventricular myocardium. Am J Physiol. 1993;265:H2094–H2098.
    1. Kobzik L., Stringer B., Balligand J.L., Reid M.B., Stamler J.S. Endothelial type nitric oxide synthase in skeletal muscle fibers: mitochondrial relationships. Biochem Biophys Res Commun. 1995;211:375–381.
    1. Zhou L.Z., Johnson A.P., Rando T.A. NF kappa B and AP-1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. Free Radic Biol Med. 2001;31:1405–1416.
    1. Dröge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.
    1. Jackson M.J. Free radicals generated by contracting muscle: by-products of metabolism or key regulators of muscle function? Free Radic Biol Med. 2008;44:132–141.
    1. Powers S.K., Radak Z., Ji L.L. Exercise-induced oxidative stress: past, present and future. J Physiol. 2016;594:5081–5092.
    1. Jackson M.J., Vasilaki A., McArdle A. Cellular mechanisms underlying oxidative stress in human exercise. Free Radic Biol Med. 2016;98:13–17.
    1. Espinosa A., Leiva A., Peña M., Müller M., Debandi A., Hidalgo C. Myotube depolarization generates reactive oxygen species through NAD(P)H oxidase; ROS-elicited Ca2+ stimulates ERK, CREB, early genes. J Cell Physiol. 2006;209:379–388.
    1. Javeshghani D., Magder S.A., Barreiro E., Quinn M.T., Hussain S.N. Molecular characterization of a superoxide-generating NAD(P)H oxidase in the ventilatory muscles. Am J Respir Crit Care Med. 2002;165:412–418.
    1. Sakellariou G.K., Lightfoot A.P., Earl K.E., Stofanko M., McDonagh B. Redox homeostasis and age-related deficits in neuromuscular integrity and function. J Cachexia Sarcopenia Muscle. 2017;8:881–906.
    1. Sakellariou G.K., Vasilaki A., Palomero J., Kayani A., Zibrik L., McArdle A. Studies of mitochondrial and nonmitochondrial sources implicate nicotinamide adenine dinucleotide phosphate oxidase(s) in the increased skeletal muscle superoxide generation that occurs during contractile activity. Antioxid Redox Signal. 2013;18:603–621.
    1. Xia R., Webb J.A., Gnall L.L., Cutler K., Abramson J.J. Skeletal muscle sarcoplasmic reticulum contains a NADH-dependent oxidase that generates superoxide. Am J Physiol Cell Physiol. 2003;285:C215–C221.
    1. Boveris A., Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J. 1973;134:707–716.
    1. Kavazis A.N., Talbert E.E., Smuder A.J., Hudson M.B., Nelson W.B., Powers S.K. Mechanical ventilation induces diaphragmatic mitochondrial dysfunction and increased oxidant production. Free Radic Biol Med. 2009;46:842–850.
    1. Powers S.K., Hudson M.B., Nelson W.B., Talbert E.E., Min K., Szeto H.H. Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness. Crit Care Med. 2011;39:1749–1759.
    1. Anderson E.J., Neufer P.D. Type II skeletal myofibers possess unique properties that potentiate mitochondrial H2O2 generation. Am J Physiol Cell Physiol. 2006;290:C844–C851.
    1. Zuo L., FL Christofi F.L., Wright V.P., Bao S., Clanton T.L. Lipoxygenase-dependent superoxide release in skeletal muscle. J Appl Physiol (1985) 2004;97:661–668.
    1. Zhao X., Bey E.A., Wientjes F.B., Cathcart M.K. Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. cPLA2 affects translocation but not phosphorylation of p67phox and p47phox. J Biol Chem. 2002;277:25385–25392.
    1. Nethery D., Callahan L.A., Stofan D., Mattera R., DiMarco A., Supinski G. PLA2 dependence of diaphragm mitochondrial formation of reactive oxygen species. J Appl Physiol (1985) 2000;89:72–80.
    1. Gong M.C., Arbogast S., Guo Z., Mathenia J., Su W., Reid M.B. Calcium-independent phospholipase A2 modulates cytosolic oxidant activity and contractile function in murine skeletal muscle cells. J Appl Physiol. 2006;100:399–405.
    1. Nethery D., Stofan D., Callahan L., DiMarco A., Supinski G. Formation of reactive oxygen species by the contracting diaphragm is PLA2 dependent. J Appl Physiol (1985) 1999;87:792–800.
    1. Ward C.W., Prosser B.L., Lederer W.J. Mechanical stretch-induced activation of ROS/RNS signaling in striated muscle. Antioxid Redox Signal. 2014;20:929–936.
    1. Ferreira L.F., Laitano O. Regulation of NADPH oxidases in skeletal muscle. Free Radic Biol Med. 2016;98:18–28.
    1. Pearson T., Kabayo T., Ng R., Chamberlain J., McArdle A., Jackson M.J. Skeletal muscle contractions induce acute changes in cytosolic superoxide, but slower responses in mitochondrial superoxide and cellular hydrogen peroxide. PLoS One. 2014;9:e96378. doi: 10.1371/journal.pone.0096378.
    1. Michaelson L.P., Shi G., Ward C.W., Rodney G.G. Mitochondrial redox potential during contraction in single intact muscle fibers. Muscle Nerve. 2010;42:522–529.
    1. Lawler J.M., Powers S.K., Visser T., Van Dijk H., Kordus M.J., Ji L.L. Acute exercise and skeletal muscle antioxidant and metabolic enzymes: effects of fiber type and age. Am J Physiol. 1993;265:R1344–R1350.
    1. Quindry J.C., Stone W.L., King J., Broeder C.E. The effects of acute exercise on neutrophils and plasma oxidative stress. Med Sci Sports Exerc. 2003;35:1139–1145.
    1. Vincent H.K., Powers S.K., Demirel H.A., Coombes J.S., Naito H. Exercise training protects against contraction-induced lipid peroxidation in the diaphragm. Eur J Appl Physiol Occup Physiol. 1999;79:268–273.
    1. Vincent H.K., Powers S.K., Stewart D.J., Demirel H.A., Shanely R.A., Naito H. Short-term exercise training improves diaphragm antioxidant capacity and endurance. Eur J Appl Physiol. 2000;81:67–74.
    1. Tryfidou D.V., McClean C., Nikolaidis M.G., Davison G.W. DNA damage following acute aerobic exercise: a systematic review and meta-analysis. Sports Med. 2019;50:103–127.
    1. Reid M.B. Invited review: redox modulation of skeletal muscle contraction: what we know and what we don't. J Appl Physiol. 2001;90:724–731.
    1. Clanton T.L., Zuo L., Klawitter Oxidants and skeletal muscle function: physiologic and pathophysiologic implications. Proc Soc Exp Biol Med. 1999;222:253–262.
    1. Powers S.K., Ji L.L., Kavazis A.N., Jackson M.J. Reactive oxygen species: impact on skeletal muscle. Compr Physiol. 2011;1:941–969.
    1. Reid M.B., Andrade F.H., Balke C.W., Esser K.A. Redox mechanisms of muscle dysfunction in inflammatory disease. Phys Med Rehabil Clin N Am. 2005;16:925–949.
    1. Reid M.B., Haack K.E., Franchek K.M., Valberg P.A., Kobzik L., West M.S. Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro. J Appl Physiol (1985) 1992;73:1797–1804.
    1. Reid M.B., Khawli F.A., Moody M.R. Reactive oxygen in skeletal muscle. III. Contractility of unfatigued muscle. J Appl Physiol (1985) 1993;75:1081–1087.
    1. Reid M.B., Stokić D.S., Koch S.M., Khawli F.A., Leis A.A. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Invest. 1994;94:2468–2474.
    1. Supinski G.S., Stofan D., Ciufo R., DiMarco A. N-acetylcysteine administration alters the response to inspiratory loading in oxygen-supplemented rats. J Appl Physiol (1985) 1997;82:1119–1125.
    1. Andrade F.H., Reid M.B., Allen D.G., Westerblad H. Effect of hydrogen peroxide and dithiothreitol on contractile function of single skeletal muscle fibres from the mouse. J Physiol. 1998;509:565–575.
    1. Moopanar T.R., Allen D.G. Reactive oxygen species reduce myofibrillar Ca2+ sensitivity in fatiguing mouse skeletal muscle at 37°C. J Physiol. 2005;564:189–199.
    1. Feng W., Liu G., Allen P.D., Pessah I.N. Transmembrane redox sensor of ryanodine receptor complex. J Biol Chem. 2000;275:35902–35907.
    1. Marengo J.J., Hidalgo C., Bull R. Sulfhydryl oxidation modifies the calcium dependence of ryanodine-sensitive calcium channels of excitable cells. Biophys J. 1998;74:1263–1277.
    1. Posterino G.S., Cellini M.A., Lamb G.D. Effects of oxidation and cytosolic redox conditions on excitation-contraction coupling in rat skeletal muscle. J Physiol. 2003;547:807–823.
    1. Sun J., Xu L., Eu J.P., Stamler J.S., Meissner G. Classes of thiols that influence the activity of the skeletal muscle calcium release channel. J Biol Chem. 2001;276:15625–15630.
    1. Brotto M.A., Nosek T.M. Hydrogen peroxide disrupts Ca2+ release from the sarcoplasmic reticulum of rat skeletal muscle fibers. J Appl Physiol (1985) 1996;81:731–737.
    1. McKenna M.J., Medved I., Goodman C.A., Brown M.J., Bjorksten A.R., Murphy K.T. N-acetylcysteine attenuates the decline in muscle Na+,K+-pump activity and delays fatigue during prolonged exercise in humans. J Physiol. 2006;576:279–288.
    1. Gomez-Cabrera M.C., Domenech E., Romagnoli M., Arduini A., Borras C. Pallardo FV, et al. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr. 2008;87:142–149.
    1. Pastor R., Tur J.A. Antioxidant supplementation and adaptive response to training: a systematic review. Curr Pharm Des. 2019;25:1889–1912.
    1. Ristow M., Zarse K., Oberbach A., Klöting N., Birringer M., Kiehntopf M. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106:8665–8670.
    1. Powers S.K., Duarte J., Kavazis A.N., Talbert E.E. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol. 2010;95:1–9.
    1. Powers S.K., Talbert E.E., Adhihetty P.J. Reactive oxygen and nitrogen species as intracellular signals in skeletal muscle. J Physiol. 2011;589:2129–2138.
    1. Smuder A.J., Min K., Hudson M.B., Kavazis A.N., Kwon O.S., Nelson W.B. Endurance exercise attenuates ventilator-induced diaphragm dysfunction. J Appl Physiol (1985) 2012;112:501–510.
    1. Vargas-Mendoza N., Morales-González Á., Madrigal-Santillán E.O., Madrigal-Bujaidar E., Álvarez-González I., García-Melo L.F. Antioxidant and adaptative response mediated by Nrf2 during physical exercise. Antioxidants (Basel) 2019;8:E196. doi: 10.3390/antiox8060196.
    1. Tonelli C., Chio I.I.C., Tuveson D.A. Transcriptional regulation by Nrf2. Antioxid Redox Signal. 2018;29:1727–1745.
    1. Ismaeel A., Holmes M., Papoutsi E., Panton L., Koutakis P. Resistance training, antioxidant status, and antioxidant supplementation. Int J Sport Nutr Exerc Metab. 2019;29:539–547.
    1. Leslie N.R., Bennett D., Lindsay Y.E., Stewart H., Gray A., Downes C.P. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 2003;22:5501–5510.
    1. Ito N., Ruegg U.T., Kudo A., Miyagoe-Suzuki Y., Takeda S. Activation of calcium signaling through Trpv1 by nNOS and peroxynitrite as a key trigger of skeletal muscle hypertrophy. Nat Med. 2013;19:101–106.
    1. de Sousa C.V., Sales M.M., Rosa T.S., Lewis J.E., de Andrade R.V., Simões H.G. The antioxidant effect of exercise: a systematic review and meta-analysis. Sports Med. 2017;47:277–293.
    1. Di Meo S., Napolitano G., Venditti P. Mediators of physical activity protection against ROS-linked skeletal muscle damage. Int J Mol Sci. 2019;20:E3024. doi: 10.3390/ijms20123024.
    1. Nocella C., Cammisotto V., Pigozzi F., Borrione P., Fossati C., D'Amico A. Impairment between oxidant and antioxidant systems: short- and long-term implications for athletes' health. Nutrients. 2019;11:E1353. doi: 10.3390/nu11061353.
    1. Radak Z., Ishihara K., Tekus E., Varga C., Posa A., Balogh L. Exercise, oxidants, and antioxidants change the shape of the bell-shaped hormesis curve. Redox Biol. 2017;12:285–290.
    1. Calabrese E.J., Baldwin L.A. Chemical hormesis: its historical foundations as a biological hypothesis. Toxicol Pathol. 1999;27:195–216.
    1. Mattson M.P. Hormesis defined. Ageing Res Rev. 2008;7:1–7.
    1. Radak Z., Chung H.Y., Goto S. Exercise and hormesis: oxidative stress-related adaptation for successful aging. Biogerontology. 2005;6:71–75.
    1. Musci R.V., Hamilton K.L., Linden M.A. Exercise-induced mitohormesis for the maintenance of skeletal muscle and healthspan extension. Sports (Basel) 2019;7:E170. doi: 10.3390/sports7070170.
    1. Korsager Larsen M., Matchkov V.V. Hypertension and physical exercise: role of oxidative stress. Medicina (Kaunas) 2016;52:19–27.
    1. Paillard T., Rolland Y., de Souto Barreto P. Protective effects of physical exercise in Alzheimer's disease and Parkinson's disease: a narrative review. J Clin Neurol. 2015;11:212–219.
    1. Hojman P., Gehl J., Christensen J.F., Pedersen B.K. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab. 2018;27:10–21.
    1. Moore S.C., Lee I.M., Weiderpass E., Campbell P.T., Sampson J.N., Kitahara C.M. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med. 2016;176:816–825.
    1. Holmes M.D., Chen W.Y., Feskanich D., Kroenke C.H., Colditz G.A. Physical activity and survival after breast cancer diagnosis. JAMA. 2005;293:2479–2486.
    1. Kenfield S.A., Stampfer M.J., Giovannucci E., Chan J.M. Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study. J Clin Oncol. 2011;29:726–732.
    1. Meyerhardt J.A., Giovannucci E.L., Holmes M.D., Chan A.T., Chan J.A., Colditz G.A. Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol. 2006;24:3527–3534.
    1. Thomas R.J., Kenfield S.A., Jimenez A. Exercise-induced biochemical changes and their potential influence on cancer: a scientific review. Br J Sports Med. 2017;51:640–644.
    1. Lavie C.J., Arena R., Swift D.L., Johannsen N.M., Sui N.M., Lee D.C. Exercise and the cardiovascular system: clinical science and cardiovascular outcomes. Circ Res. 2015;117:207–219.
    1. Foulds H.J., Bredin S.S., Charlesworth S.A., Ivey A.C., Warburton D.E. Exercise volume and intensity: a dose-response relationship with health benefits. Eur J Appl Physiol. 2014;114:1563–1571.
    1. Barnham K.J., Masters C.L., Bush C.L. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov. 2004;3:205–214.
    1. Lin M.T., Beal M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443:787–795.
    1. Liu Z., Zhou T., Ziegler A.C., Dimitrion P., Zuo L. Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxid Med Cell Longev. 2017;2017 doi: 10.1155/2017/2525967.
    1. Lucas S.J., Cotter J.D., Brassard P., Bailey D.M. High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence. J Cereb Blood Flow Metab. 2015;35:902–911.
    1. Blair S.N., Kampert J.B., Kohl H.W., 3rd., Barlow C.E., Macera C.A., Paffenbarger R.S., Jr. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996;276:205–210.
    1. Harber M.P., Kaminsky L.A., Arena R., Blair S.N., Franklin B.A., Myers J. Impact of cardiorespiratory fitness on all-cause and disease-specific mortality: advances since 2009. Prog Cardiovasc Dis. 2017;60:11–20.
    1. Lee I.M., Skerrett P.J. Physical activity and all-cause mortality: what is the dose-response relation? Med Sci Sports Exerc. 2001;33(Suppl. 6):S459–S471.

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