We breakdown what happens to your body during intense exercise and why trying to eliminate cell oxidisation is not recommended.
By Bill Willis PHDc and John Meadows CSCS, CISSN. Athlete Chris Fitzpatrick. Photography by Slade Mansfield (www.purephotography.co.za).
Hitting the weights in the gym, doing cardio, and even sitting here reading this article, the billions of cells in your body are burning ATP, which supplies the energy needed to run things. During cellular respiration, energy from food is “burned”, or more correctly, oxidised, to drive the cellular machinery that makes ATP. This isn’t all that different to what happens in the internal combustion engine of your car, where the fuel (gasoline) is oxidised to make the energy to get from point A to point B. The end-result of cellular respiration is ATP production driven by oxidation, where electrons originally stored in the chemical bonds of food are transferred to molecular oxygen. Large amounts of energy are generated in this process, but it comes at a cost. Molecules are “happy” when they have even numbers of electrons, paired up in their outer electron shells. Pushing all those electrons around during cellular respiration results in the production of highly reactive molecules with one or more unpaired electrons called free radicals. Free radicals are “electron-hungry”, and will react with almost anything they come in contact with to get back to a state where all their electrons are paired, making them potentially destructive to the cell. Most free radicals are various forms of oxygen, also referred to as reactive oxygen species (ROS).
To meet increased demands of ATP synthesis during exercise, ROS production increases substantially; this can result in oxidative damage to proteins and lipids in contracting muscle tissue. Overproduction of ROS can result in oxidative stress, which plays a role in the progression of a number of chronic diseases including type II diabetes. Based on this, you might think that antioxidant supplementation would be a no-brainer. ROS are destructive, so antioxidant supplementation during any intense training program would seem like a requirement. Until recently, most of the scientific community would have agreed, but it turns out the opposite may be the case. Recent discoveries have challenged this idea, suggesting that supplementing with antioxidants may not only hinder training progress, but may also increase the likelihood for disease or even decrease lifespan!
What Is Oxidative Stress?
The main ROS in the cell are free radicals such as superoxide anion (O2·-) and the non-radical hydrogen peroxide (H2O2). Free radicals and hydrogen peroxide are normal bi-products of the oxidative phosphorylation chemistry that occurs in mitochondria to drive ATP synthesis. During oxidative phosphorylation, energy in the form of electrons is shuttled through the mitochondrial electron transport chain via a series of oxidation/reduction (redox) reactions to molecular oxygen. The energy generated during this process is stored as chemical energy by linking an adenosine molecule to three phosphate molecules, creating ATP.
A large amount of free radicals are produced under normal cellular conditions; as much as 2-5% of total oxygen consumed by mitochondria is converted to superoxide (1, 2). Superoxide can be converted to the less reactive hydrogen peroxide by the enzyme superoxide dismutase (SOD). Hydrogen peroxide is finally converted to oxygen and water by cellular antioxidant enzymes such as catalase, thioredoxin, and glutathione peroxidase (GPX). In chronic diseases the generation of an excess of ROS can overwhelm natural antioxidant defense mechanisms, driving the pathologies of these diseases. In the case of diabetes or obesity, excess ROS production alters certain cell signaling pathways which ultimately suppress insulin receptor signaling, causing insulin resistance. Given the relationship between ROS and disease, it would seem like ROS production during exercise would be a metabolic roadblock to getting bigger and leaner. Recent scientific discoveries have suggested that we may have it all wrong when it comes to ROS and exercise, however.
“Pathological” vs. “Physiological” ROS
An important distinction needs to be made between “pathological” and “physiological” ROS. While excess ROS production causes oxidative stress and disease, ROS are not bad-in and of themselves. In recent years it has been discovered that low levels of “physiological” ROS are actually required for normal cell function. A large number of the cell signaling cascades which control muscle growth and fat loss are dependent on ROS production. In addition to the mitochondria, physiological ROS are produced by the enzyme NADPH oxidase (Nox). Nox enzymes generate superoxide which, along with hydrogen peroxide has been discovered to be important for an increasingly large number of redox-sensitive cell signaling cascades such as the ERK/MAPK pathway, which is important for muscle repair after intense training sessions. In the case of cellular oxidation/ROS production, the dose makes the poison; while uncontrolled oxidation is a driver of disease, physiological ROS production is essential for normal cellular function. If you take away physiological ROS production during exercise, and the training response isn’t optimal; fat loss and muscle gain is compromised. The takeaway here is that managing inflammation is probably not bad, trying to eliminate it most certainly is.
Oxidative stress is driven by inflammation, which is the link between pathological and physiological ROS. A pro-inflammatory metabolic environment directly induces ROS production, which causes disturbances in cellular calcium-handling. Increases in calcium flux amplify the activity of dehydrogenase enzymes located in the mitochondrial electron transport chain which further increases ROS production. This, in-turn, can cause cellular damage, increasing inflammation. The end-result of this process is an inflammation-driven “feed forward” loop, amplifying ROS production to pathological levels.
Oxidation, antioxidants, and muscle damage
The first evidence that contracting skeletal muscles produce free radicals was published in 1982, which suggested for the first time that ROS production during exercise is potentially damaging to muscle (3). Throughout the 1980’s work in this field was focused on the role of antioxidant nutrients in the protection of cells from oxidative damage. During this period it was found that depletion of vitamin E increased the risk of contraction-induced membrane damage in skeletal muscle (4, 5). Based on this and related work, scientists reasoned that vitamin E and other antioxidant nutrients may enhance recovery by preventing tissue damage and contractile dysfunction during exercise. Related work has continued in research labs to present day. While it is clear that the kind of acute oxidative stress that occurs during exercise is potentially damaging to muscle tissue, recent research suggests that there is much more to this story. The idea looks great on paper; oxidation causes cellular damage, so reducing oxidation in working muscle tissue must be a good thing. This led millions of otherwise well-informed people (including the author) to supplement copious amounts of antioxidants in hopes to recover better from intense training (Just crushed the legs… better take and extra 10,000mg vitamin C!). Although vitamin C, vitamin E and other antioxidants have been suggested to decrease markers of oxidative damage in muscle (6, 7), evidence for any positive effects of antioxidant supplementation on contraction-induced muscle damage has never been found (8). So antioxidant supplementation fails to deliver in the real-world as a recovery enhancer, but there is more to this story and it may actually be harmful!
Exercise and endogenous antioxidants
Part of the adaptive response to exercise involves up-regulation of the expression and activity of endogenous antioxidant enzymes. This gives the cell an increased capacity to handle oxidative stress. Among the antioxidant enzymes in skeletal muscle, SOD activity has consistently been shown to increase with training in an intensity-dependent manner (9-11). GPX activity also naturally increases as a result of endurance training (10-15). In human and animal studies, antioxidants suppress the natural up-regulation of cellular antioxidant enzymes in response to training (12, 16-18). Conversely, exercise training in animals fed an antioxidant deficient diet (vitamin E, selenium) has been shown to induce greater levels of antioxidant adaptation than those fed a normal diet (12, 16, 17). While animal studies such as these are informative, they need to be interpreted with a degree of caution; antioxidants are still required for optimal cellular function and health. In spite of this caveat, the evidence is clear; supplementation with even moderate amounts of antioxidants suppresses an important component of the adaptive response to exercise.
Elevated antioxidant enzyme activities induced by training have potential benefits outside of the gym; exercise may slow the aging process and play a direct role in the prevention of a number of diseases associated with oxidative stress. Antioxidant supplementation, by inhibiting the exercise-induced up-regulation of endogenous antioxidant enzymes, may ultimately increase the likelihood for disease by limiting tolerance for oxidative stress. A large number of prevention randomised trials have been conducted to assess the benefit (or harm) of antioxidant supplementation in humans. These trials have failed to demonstrate that β-carotene, vitamin A, or vitamin E decrease mortality, and some studies have suggested that mortality may actually increase (19-22).
Antioxidants and insulin sensitivity
ROS and training adaptations associated with improvements in insulin sensitivity are intimately linked. In addition to increasing muscular strength and size, intense training improves glucose metabolism by enhancing insulin sensitivity. Insulin sensitivity is directly linked to conditioning; the more insulin sensitive you are, the less insulin is needed and the leaner you will be in general. For this reason, leaner body types tend to have lower insulin levels. Chronic/inflammation-driven production of ROS causes insulin resistance in diabetes and obesity (23). In spite of this, it has recently been discovered that ROS production is actually essential for optimal insulin sensitivity (24). A research group recently examined the effects of antioxidant supplementation on the insulin-sensitivity enhancing effects of exercise in humans (18). In this study the effects of a combination of vitamin C (1000mg/day) and vitamin E (400IU/day) on insulin sensitivity were evaluated before and after a 4 week period of exercise (5 days/week of cardio + weight training). The exercise protocol increased insulin sensitivity only in the subjects not receiving the antioxidants. Likewise, it was also found that exercise increased the expression of the endogenous antioxidant enzymes SOD and GPX only in the non-antioxidant subjects. The striking thing about this particular study was that the dosing was actually on the low to moderate end of what people are typically taking. This suggests that literally millions of people may be unknowingly hindering their training progress with antioxidant supplementation. This is particularly true for those who are starting out overweight. Dieting can be an uphill battle for people who are insulin resistant. Weight loss becomes as much of an “energy storage” issue as an “energy intake” issue in these people, so antioxidant supplementation may be particularly counterproductive in these cases. Taken together, the important role of insulin in the regulation of glucose metabolism and protein synthesis suggests that bulk suppression of acute ROS formation during exercise with even moderate doses of supplemental antioxidants can potentially have a big negative effect on the training response.
Antioxidants and muscle growth
Acute ROS production during exercise is essential for muscle growth. Hypertrophic remodeling in muscle is associated with a number of redox-sensitive signaling pathways, suggesting that acute exercise-induced oxidation plays a central role in this process. Muscular hypertrophy induced by intense training causes an increase in protein synthesis (25, 26). Cellular rates of protein synthesis are regulated by an enzyme complex referred to as the mammalian target of rapamycin complex (mTORC). There is a direct relationship between training loads, muscle growth, and mTORC activation (27). Physiological ROS production is essential for optimal mTORC signaling. When ROS production is inhibited in muscle, mTORC signaling is significantly reduced (28). This suggests that antioxidants may directly inhibit muscle growth in response to intense training. While this has not yet been established in vivo, recent in vitro evidence suggests that this may be the case. IGF-1 is a potent growth factor that stimulates hypertrophy and inhibits muscle breakdown. A recent study found that physiological ROS production is required for IGF-1 signaling in cultured myocyte (muscle) cells. Treatment of the cultured myocytes with antioxidants inhibited hypertrophy by eliminating ROS production, demonstrating that ROS production is necessary for IGF-1 induced hypertrophy in vitro (29).
Conclusions and practical recommendations:
As much as one third of adults in high-come countries consume antioxidant supplements (30). In spite of their best intentions, these people may be limiting their training results, rendering themselves more susceptible to chronic disease, and even shortening their lifespan. This is not to suggest that antioxidants such as β carotene, vitamin C, vitamin E, and selenium are not required; as essential micronutrients they need to be obtained from the diet. There is a positive association between high intakes of antioxidant-rich fruits and vegetables and delayed aging, reduced cancer risk, and reduced risk for cardiovascular diseases (31, 32). It is not known at this point why antioxidant supplements can’t reproduce the effects of those obtained from a well-balanced diet, and evidence for their potentially negative effects is ever-increasing.
There are several possible explanations for the potentially harmful effects of antioxidant supplements. Low moderate to ROS levels are required for normal cellular function. Insulin sensitivity, muscular hypertrophy, and endogenous antioxidant enzyme up-regulation, all of which are important components of the training response, are dependent on ROS production. Physiological ROS are precisely regulated in space-and time in the cell. Because ROS production is required for muscular hypertrophy, it is not surprising that mitochondria are typically located in close proximity to localised sites of protein synthesis (33). Likewise, NADPH oxidases, which are required for optimal insulin signaling, also localise to very specific sites in the cell (8). Bulk suppression of ROS with antioxidant supplements may disrupt the precise spatial and temporal regulation of physiological ROS, throwing a wrench in the finely tuned redox –sensitive signaling machinery essential for optimal cellular function.
Obtain antioxidants exclusively from a well-balanced diet
We haven’t outsmarted nature yet. Everything we need in terms of antioxidants is packaged in antioxidant rich foods just the way nature intended it; with optimal bioavailability and biological effect. With a well-balanced diet, we are well-equipped to deal with the acute increases in ROS production generated during intense training. ROS production under these circumstances is actually critical for optimal training adaptations. The take-home message here is to get your antioxidants from whole-foods as part of a well-balanced diet, rather than from supplements.
Sample food sources of antioxidants include:
Red palm oil – Contains all tocopherols and tocotrienols of Vitamin E – EXCELLENT!
Organic free range eggs – Vitamin E
Kiwi Fruit – Very high in Vitamin C
Oranges, Strawberries – also good sources of vitamin C.
Brazil nuts – great source of selenium (potent antioxidant)
Add in some veggies too…like Kale
There are supplements that can help recycle antioxidants in your body and work effectively with your diet, but that is another story for another day! Eat well, eat nutritiously and your body will take care of itself.
1. Boveris A, Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 1973;134:707-16.
2. Loschen G, Azzi A, Richter C, Flohe L. Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 1974;42:68-72.
3. Davies KJ, Quintanilha AT, Brooks GA, Packer L. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun 1982;107:1198-205.
4. Jackson MJ, Edwards RH, Symons MC. Electron spin resonance studies of intact mammalian skeletal muscle. Biochim Biophys Acta 1985;847:185-90.
5. Jackson MJ, Jones DA, Edwards RH. Vitamin E and skeletal muscle. Ciba Found Symp 1983;101:224-39.
6. Goldfarb AH, McIntosh MK, Boyer BT, Fatouros J. Vitamin E effects on indexes of lipid peroxidation in muscle from DHEA-treated and exercised rats. J Appl Physiol 1994;76:1630-5.
7. Kanter MM, Nolte LA, Holloszy JO. Effects of an antioxidant vitamin mixture on lipid peroxidation at rest and postexercise. J Appl Physiol 1993;74:965-9.
8. Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 2008;88:1243-76.
9. Higuchi M, Cartier LJ, Chen M, Holloszy JO. Superoxide dismutase and catalase in skeletal muscle: adaptive response to exercise. J Gerontol 1985;40:281-6.
10. Leeuwenburgh C, Fiebig R, Chandwaney R, Ji LL. Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems. Am J Physiol 1994;267:R439-R445.
11. Powers SK, Criswell D, Lawler J, Ji LL, Martin D, Herb RA, et al. Influence of exercise and fiber type on antioxidant enzyme activity in rat skeletal muscle. Am J Physiol 1994;266:R375-R380.
12. Ji LL, Stratman FW, Lardy HA. Antioxidant enzyme systems in rat liver and skeletal muscle. Influences of selenium deficiency, chronic training, and acute exercise. Arch Biochem Biophys 1988;263:150-60.
13. Ji LL, Stratman FW, Lardy HA. Enzymatic down regulation with exercise in rat skeletal muscle. Arch Biochem Biophys 1988;263:137-49.
14. Laughlin MH, Simpson T, Sexton WL, Brown OR, Smith JK, Korthuis RJ. Skeletal muscle oxidative capacity, antioxidant enzymes, and exercise training. J Appl Physiol 1990;68:2337-43.
15. Lawler JM, Powers SK, Visser T, Van DH, Kordus MJ, Ji LL. Acute exercise and skeletal muscle antioxidant and metabolic enzymes: effects of fiber type and age. Am J Physiol 1993;265:R1344-R1350.
16. Leeuwenburgh C, Ji LL. Glutathione depletion in rested and exercised mice: biochemical consequence and adaptation. Arch Biochem Biophys 1995;316:941-9.
17. Chang CK, Huang HY, Tseng HF, Hsuuw YD, Tso TK. Interaction of vitamin E and exercise training on oxidative stress and antioxidant enzyme activities in rat skeletal muscles. J Nutr Biochem 2007;18:39-45.
18. Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 2009;106:8665-70.
19. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003;361:2017-23.
20. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004;364:1219-28.
21. Miller ER, III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
22. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842-57.
23. Kim JA, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res 2008;102:401-14.
24. Loh K, Deng H, Fukushima A, Cai X, Boivin B, Galic S, et al. Reactive oxygen species enhance insulin sensitivity. Cell Metab 2009;10:260-72.
25. Wong TS, Booth FW. Protein metabolism in rat gastrocnemius muscle after stimulated chronic concentric exercise. J Appl Physiol 1990;69:1709-17.
26. Chesley A, MacDougall JD, Tarnopolsky MA, Atkinson SA, Smith K. Changes in human muscle protein synthesis after resistance exercise. J Appl Physiol 1992;73:1383-8.
27. Baar K, Esser K. Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol 1999;276:C120-C127.
28. Li M, Zhao L, Liu J, Liu A, Jia C, Ma D, et al. Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling. Cell Signal 2010;22:1469-76.
29. Handayaningsih AE, Iguchi G, Fukuoka H, Nishizawa H, Takahashi M, Yamamoto M, et al. Reactive oxygen species play an essential role in IGF-I signaling and IGF-I-induced myocyte hypertrophy in C2C12 myocytes. Endocrinology 2011;152:912-21.
30. Millen AE, Dodd KW, Subar AF. Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey results. J Am Diet Assoc 2004;104:942-50.
31. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992;18:1-29.
32. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 1993;90:7915-22.
33. Margeot A, Garcia M, Wang W, Tetaud E, di Rago JP, Jacq C. Why are many mRNAs translated to the vicinity of mitochondria: a role in protein complex assembly? Gene 2005;354:64-71.