KEY POINTS

• A radical (free radical) is a highly reactive molecule or fragment of a molecule that contains an unpaired electron. Radicals serve as oxidants when they remove electrons from other molecules and they can produce cellular damage.
• To protect against radical-mediated damage, cells contain endogenous antioxidants that scavenge or neutralize radicals. Additionally, dietary antioxidants interact with endogenous antioxidants to form a cooperative network of cellular protection against radicals.
• Vigorous exercise promotes the production of radicals in contracting muscles. Radical production increases as exercise progresses in intensity and duration; this can contribute to fatigue during submaximal exercise lasting more than 30 minutes.
• Prolonged or intense exercise can cause an imbalance between radical production and antioxidant defense systems in muscles, leading to damage of muscle proteins and lipids (i.e., oxidative stress).
• Numerous studies indicate that supplementation with low levels of common dietary antioxidants does not delay muscular fatigue. Nonetheless, emerging research suggests that administration of specific types of antioxidants can delay radical-mediated muscular fatigue in humans.
• It is currently unclear whether prolonged and vigorous exercise training increases the requirements for the dietary intake of antioxidants.

INTRODUCTION

Radicals (also called free radicals) are molecules or fragments of molecules that contain unpaired electrons in their outer orbitals (Halliwell & Gutteridge, 2007). These unpaired electrons cause molecular instability; therefore, radicals are highly reactive molecules that promote oxidative damage to proteins, lipids, and DNA. Radical-mediated damage to cellular constituents is called oxidative stress, and high levels of oxidative stress can lead to cellular dysfunction and in extreme cases, cell death.

Interestingly, although regular physical exercise provides many health benefits, it results in increased production of radicals. Indeed, prolonged and/or intense exercise can lead to oxidative stress in skeletal muscles, blood, and perhaps other tissues. Importantly, exercise-induced oxidative stress can reduce maximal force production in skeletal muscles and promote fatigue during prolonged exercise sessions. Fortunately, cells contain a natural defense system (i.e., enzymatic and non-enzymatic antioxidants) to protect against radical-mediated damage. Moreover, dietary antioxidants (e.g., vitamin C and vitamin E) cooperate with endogenous antioxidant defense systems to form a united antioxidant network in muscle fibers.

The objective of this review is to provide a brief synopsis of exercise-induced oxidative stress and the requirement for dietary antioxidants. We will begin with an overview of exercise-induced oxidative stress and later discuss common dietary antioxidants and the conundrum of whether intense exercise training increases the need for dietary antioxidants.

RESEARCH REVIEW

EXERCISE-INDUCED RADICAL PRODUCTION

It is clear that muscular exercise induces radical production and that contracting skeletal muscles are a major source of these radicals (McArdle et al., 2002). The magnitude of exercise-induced radical production is influenced by several factors, including the intensity and duration of exercise and the environmental conditions. Specifically, skeletal muscle radical production increases as a function of both the exercise intensity and duration. Moreover, contracting skeletal muscles produce more radicals during exercise in hot environments or at high altitude (i.e., >2,000 m) (Arbogast & Reid, 2004; Clanton, 2007; Radak et al., 1997). Therefore, the extent of exercise-induced radical production can range from relatively low to high levels, depending upon the exercise conditions.

Although contracting skeletal muscles produce radicals, exercise bouts do not always result in oxidative damage to muscles. For example, exercise of low intensity and short duration does not generally promote oxidative stress in skeletal muscles. Nonetheless, prolonged exercise performed at moderate-to-high intensities often results in oxidative damage in skeletal muscles of untrained persons (Powers et al., 2004). Note, however, that highly trained endurance athletes have well-adapted endogenous antioxidant buffer systems in their skeletal muscles that resist exercise-induced oxidative stress (Powers et al., 1999). Therefore, whether an exercise bout results in oxidative stress depends not only on the intensity and duration of exercise but also on the exercise training status of the individual.

RADICALS AND MUSCLE FATIGUE

Muscle fatigue is defined as a reduction in the ability of a muscle to generate force. Fatigue can occur during a wide variety of sporting events (e.g., 400-m run, marathon, soccer, etc.) and during intense exercise training sessions. Muscle fatigue is a multifactorial process, and the specific causes of fatigue can vary due to the environmental conditions and the type of exercise performed (Hargreaves, 2005). Growing evidence indicates that radical production in skeletal muscles contributes to fatigue during prolonged exercise (i.e., events lasting >30 min). In the following paragraphs, we discuss the role that radicals play in muscle fatigue during endurance exercise.

During exercise, radical production increases in contracting skeletal muscles due to activation of several radical producing pathways. Low levels of radicals play an important signaling role in the regulation of muscle contractile function. Indeed, low levels of oxidants (i.e., radicals) in contracting skeletal muscles are a requirement to achieve optimum force production. In contrast, high levels of radicals contribute to exercise-induced muscle fatigue. For example, well-controlled animal studies indicate that scavenging or neutralizing such radicals via antioxidants delays muscle fatigue during prolonged submaximal exercise (Reid, 2001, 2008). In contrast, antioxidant scavengers of radicals are not effective in delaying muscle fatigue in animals during high intensity exercise (Reid et al., 1992a; Matuszczak et al., 2005). Finally, studies examining the effects of antioxidants on muscle performance during recovery from fatiguing exercise are inconsistent; some reports indicate a faster recovery of force production (Diaz et al., 1998), whereas others failed to show a faster recovery time (Khawli & Reid, 1994; Reid et al., 1992a, 1992b).

Do radicals contribute to exercise-induced muscular fatigue in humans? Yes. A growing number of studies indicates through the use of a strong antioxidant, that fatigue in human muscle can be delayed during submaximal exercise (Matuszczak et al., 2005; McKenna et al., 2006; Medved et al., 2004a, 2004b; Reid et al., 1994; Travaline et al., 1997). In this model N-acetylcysteine (NAC) is administered as the free-radical scavenger and has been reported to delay muscular fatigue during a variety of submaximal exercise tasks including; 1) electrically stimulated contractions of human limb muscles (Reid et al., 1994); 2) breathing against an inspiratory load (Travaline et al., 1997); 3) cycling exercise (McKenna et al., 2006; Medved et al., 2004a, 2004b); and 4) repetitive handgrip exercise (Matuszczak et al., 2005). Compared to the effects of the placebo, fatigue during exercise in this studies is diminished by 15-62%. Importantly, and consistent with the aforementioned animal studies, NAC does not appear to retard human muscle fatigue during more intense exercise at near VO2max (Diaz et al., 1994; Matuszczak et al., 2005; Medved et al., 2003). In summary, based on the model using NAC, both animal and human experiments indicate that radical accumulation during submaximal exercise may promote muscular fatigue but the role of radicals during short duration, high intensity exercise remains in question.

OVERVIEW OF ANTIOXIDANTS

Oxidative stress results from an imbalance between antioxidants and oxidants; this occurs when oxidant production exceeds the antioxidant capacity. Muscle fibers are protected against oxidant injury by a multifaceted system of endogenous and exogenous antioxidants. Specifically, a network of enzymatic and non-enzymatic antioxidants exists in both the intracellular and extracellular environments to remove radicals before they damage proteins, lipids, or DNA. To provide maximum protection against radical species, these scavengers are strategically compartmentalized throughout the cell. Several strategies are applied by both endogenous and exogenous antioxidants to protect against oxidant-mediated injury. These strategies include converting radicals into non-radicals (i.e., scavenging) and preventing the conversion of relatively inactive radicals into more damaging compounds. A brief overview of both endogenous and exogenous antioxidants follows.

ENDOGENOUS ANTIOXIDANTS

Endogenous antioxidants are synthesized in cells and include both enzymatic and non-enzymatic antioxidants. Key antioxidant enzymes include superoxide dismutase, glutathione peroxidase, and catalase (Figure 1). These antioxidant enzymes help prevent oxidative stress by scavenging radicals before they damage cellular components. The major non-enzymatic antioxidant in cells is glutathione. Glutathione can act as an independent oxidant scavenger but also works in conjunction with glutathione peroxidase to remove hydrogen peroxide (a weak oxidant) from the cell. Collectively, these cellular antioxidants work as a team to protect cells against radical-mediated damage. Importantly, regular exercise training increases the expression of both enzymatic and non-enzymatic antioxidants in the active muscles to provide protection against exercise-induced oxidative stress. Therefore, compared to untrained individuals, well-trained athletes possess higher levels of endogenous antioxidants (Powers et al., 1999).

FIGURE 1: Illustration of the major intracellular antioxidants and key dietary antioxidants that are capable of crossing cell membranes. Major intracellular antioxidant enzymes include superoxide dismutase, catalase, and glutathione peroxidase; these antioxidant enzymes work as a team to remove reactive oxygen species. Important dietary antioxidants that contribute to the total antioxidant protection network in skeletal musclesinclude vitamin E, carotenoids, vitamin C, and flavonoids.

DIETARY ANTIOXIDANTS

Numerous dietary antioxidants can also contribute to cellular protection against radicals. Important dietary antioxidants include vitamin E, vitamin C, carotenoids, and flavonoids. Vitamin E is one of the most widely distributed antioxidants in nature and protects cell membranes against radical-mediated damage (Janero, 1991; Packer, 1991). The generic term "vitamin E" refers to at least eight structural isomers of tocopherols or tocotrienols (Janero, 1991; Schaffer et al., 2005). Among these, alpha-tocopherol is the best known and possesses the most antioxidant activity (Stocker, 2007). In addition to its direct antioxidant properties, growing evidence suggests that some of the beneficial effects of vitamin E in cells resides in its ability to regulate gene expression of proteins (Azzi et al., 2003, 2004; Han et al., 2004; Schulte et al., 2006; Traber et al., 2008).

Several studies have investigated the effects of acute and chronic exercise on vitamin E levels in skeletal muscles of rodents. Unfortunately, the results are not consistent; some studies report that exercise decreases muscle vitamin E concentrations (Bowles et al., 1991; Gohil et al., 1987), whereas others conclude that neither acute nor chronic muscular activity alters muscle vitamin E levels (Coombes et al., 2002; Salminen & Vihko, 1983; Starnes et al., 1989). Studies investigating the effect of regular exercise on vitamin E in human skeletal muscle suggest that exercise does not change vitamin E levels (Tiidus & Houston, 1995; Tiidus et al., 1996).

Similar to vitamin E, carotenoids (e.g., beta-carotene) are lipid-soluble antioxidants. Because of their location in cell membranes and their radical-scavenging capacity, carotenoids are efficient biological antioxidants against radical-mediated damage to membranes (Krinsky, 1998). To date, the effect of chronic exercise on muscle levels of carotenoids has not been investigated. Hence, it is unclear whether exercise decreases muscle levels of carotenoids.

In contrast to both vitamin E and the carotenoids, vitamin C (ascorbic acid) is hydrophilic and therefore, is located in the aqueous compartment (i.e., cytosol) of the cell. As an antioxidant, vitamin C performs two key functions. First, vitamin C can directly scavenge numerous radical species (Carr & Frei, 1999); second, vitamin C plays an important role in the recycling of vitamin E. Therefore, vitamin C and vitamin E work together to protect the cell against radical-mediated damage.

Flavonoids are a family of more than 4,000 compounds found in many plants (e.g., citrus fruit, apples, grapes, etc.). At present, the antioxidant properties of many naturally occurring flavonoids have not been investigated. Nonetheless, numerous flavonoids have been studied (e.g., resveratrol), and several compounds possess important biological activities, including both anti-inflammatory and antioxidant properties. It is unknown whether regular exercise lowers cellular levels of flavonoids.

CAN COMMON DIETARY ANTIOXIDANTS DELAY MUSCULAR FATIGUE?

As discussed earlier, it is known that exercise-induced radical production contributes to muscle fatigue during prolonged exercise. Therefore, it could be hypothesized that supplementation with dietary antioxidants could delay fatigue. In this regard, numerous studies have probed the ergogenic potential of dietary antioxidants on exercise performance.

Specifically, studies have investigated whether common antioxidants such as vitamin E, vitamin C, and ubiquinone-10 can delay muscular fatigue. Collectively, these studies do not provide convincing evidence that these antioxidants are ergogenic during endurance exercise. Moreover, studies using antioxidant mixtures or selenium have not demonstrated improved exercise performance (Powers et al., 2004).

Given that the antioxidant N-acetyl-cysteine (NAC) can delay muscular fatigue during prolonged exercise, why are common dietary antioxidants incapable of providing a similar ergogenic benefit? Unfortunately, there is no definitive answer to this question, but several factors may account for the discrepancies between the studies using NAC as an antioxidant and the reports using vitamin C and vitamin E as antioxidants. For example, investigations using NAC performed dose-response studies prior to using this compound in exercise studies. In contrast, as reviewed by Powers et al. (2004), it seems unlikely that an optimal dosing strategy was identified or utilized in many studies using vitamin E or vitamin C. Clearly, much more research is required to define whether common dietary antioxidants have ergogenic potential in endurance sports.

It is important to note that high doses of antioxidants (i.e., above the optimal dose) can shift the intracellular antioxidant-oxidant (i.e., redox) balance towards a reduced state and impair skeletal muscle contractile performance (Coombes et al., 2001). Therefore, from an exercise performance perspective, indiscriminant antioxidant supplementation could be detrimental to athletic performance. To summarize, little evidence exists to recommend antioxidant supplementation for the purpose of improving athletic performance (Coombes et al., 2001).

EXERCISE AND ANTIOXIDANT REQUIREMENTS

Again, exercise-induced oxidative stress can occur during intense and prolonged exercise training sessions. Further, although unlikely to improve performance, supplementation with dietary antioxidants can retard exercise-induced oxidative damage in both blood and skeletal muscles (Ashton et al., 1999; Sen et al., 1994). Therefore, does the increased oxidant load experienced by athletes during intense training necessitate antioxidant supplementation? Arguments exist both for and against antioxidant supplementation. On the pro side, a plausible argument for antioxidant supplementation is that because intense exercise training causes an increased oxidant load on skeletal muscles and other tissues, an increased dietary intake of supplemental antioxidants seems warranted to avoid significant oxidative damage to cellular components. On the negative side, because regular exercise training increases endogenous antioxidants in muscle (Powers et al., 1999), resulting in improved protection against exercise-induced radical production, it can be argued that dietary supplementation is unnecessary. Moreover, if an athlete maintains an isocaloric diet that is well balanced with antioxidant-rich nutrients, the athlete may not require supplementary antioxidants in addition to those contained in the normal diet.

Other arguments for and against antioxidant supplementation also exist. On the pro side, it has been suggested that many athletes do not consume well-balanced diets on a daily basis and therefore these individuals could be deficient in antioxidant intake. In addition, it is possible that the recommended daily allowances of antioxidant vitamins (e.g., vitamin C and vitamin E) may not be optimal for athletes engaged in high intensity training, so higher dietary intake of these antioxidants may be required. Unfortunately, this position cannot be denied or supported by experimental evidence. On the negative side, it can be theorized that consumption of too many antioxidants can be harmful to exercise performance in two important ways. First, research suggests that exercise-induced radical production in skeletal muscle may serve as an activator of a beneficial adaptive response in muscle fibers, resulting in the increased expression of both antioxidant enzymes and heat shock proteins (McArdle et al., 2002). Hence, supplementation with high doses of antioxidants could blunt the training adaptation to exercise (Hamilton et al., 2003). Second, consuming high levels of antioxidants can impair maximal force production in skeletal muscle and therefore impede exercise performance (Coombes et al., 2001). As discussed earlier, it is well known that an optimal level of oxidants and antioxidants exists in skeletal muscle and that deviation from the optimal level can adversely affect muscle performance (Reid, 2008).

SUMMARY

Exercise promotes the production of radicals in the contracting muscles, and during prolonged/intense exercise these radicals can overwhelm muscle antioxidants, resulting in oxidative stress. To protect against radical-mediated damage, muscle cells contain endogenous antioxidants to scavenge radicals. Moreover, dietary antioxidants cooperate with endogenous antioxidants to form a supportive network of cellular protection against radicals.

It is known that radical production contributes to muscle fatigue during high intensity exercise lasting more than 30 min. Although supplementation with common dietary antioxidants such as vitamin E or vitamin C does not delay muscular fatigue, supplementation with select antioxidants (e.g., N-acetylcysteine) does retard radical-mediated muscular fatigue.

The question of whether or not athletes should use antioxidant supplements to enhance performance remains an important and unresolved issue. There are arguments for and against antioxidant supplementation, and future research will be required to establish the types and optimal combinations of antioxidants for athletes. Unfortunately, this is a complicated issue that will be difficult to investigate. Therefore, it seems likely that the subject of antioxidant supplementation for athletes will remain controversial for years to come.

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SUPPLEMENT

DO YOU NEED ANTIOXIDANT SUPPLEMENTS TO PERFORM AT YOUR BEST?

Biological antioxidants can help minimize cell damage caused by reactive oxidant chemicals called radicals. Numerous dietary antioxidant supplements are commercially available. Advertisements for these supplements often proclaim that they provide both health and performance benefits to athletes and non-athletes. However, the health benefits of antioxidant supplementation remain controversial, and only one antioxidant, N-acetyl cysteine, has been consistently shown to improve certain types of exercise performance.

Is Antioxidant Supplementation Right for You?

Are you thinking about using antioxidant supplements to improve your exercise performance? If so, consider the following points before beginning a program of supplementation:

• Because the supplement industry is not highly regulated, do not assume that the ingredients listed on the bottle label are always present in the amounts stated.
• Importantly, you should be aware that some supplements may contain substances not listed on the product label, that these additional ingredients may not provide nutritional benefits, and, in some extreme cases, these ingredients may have negative health consequences. For example, some "over-the-counter" dietary supplements have been reported to contain ephedrine, which can produce adverse side effects such as rapid heart rate and/or abnormal heart rhythms. Also, there have been instances in which dietary supplements have been contaminated with anabolic steroids, which can lead to failing a doping test.
• Supplementation with low levels of common dietary antioxidants does not improve endurance exercise performance. For example, supplementation with vitamin E and vitamin C seems to have no beneficial effect on athletic performance. In contrast, select types of antioxidants (e.g., N-acetyl-cysteine) can delay muscular fatigue and improve endurance exercise performance. However, unwanted side effects such as nausea have been reported with the use of N-acetyl-cysteine.
• Do not expect antioxidant supplementation to take the place of appropriate exercise training or to replace a well-balanced diet. Moreover, when considering the pros-and cons of dietary antioxidant supplementation, consider the fact that research has shown that an extremely high intake of dietary antioxidants can actually impair exercise performance and/or blunt some of the beneficial training adaptations that occur in skeletal muscles.

SUGGESTED ADDITIONAL RESOURCES

Vina, J., M. Gomez-Cabrera, and C. Borras. (2007). Fostering antioxidant defenses: up-regulation of antioxidant genes or antioxidant supplementation? Br J Nutr 98 (Suppl. 1), S36-40.

Milbury PE and Richer AC, (2007) "Understanding the Antioxidant Controversy — Scrutinizing the "Fountain of Youth"", Greenwood Publishing Group, Oxford, England.

Powers, S. K., DeRuisseau, K. C., Quindry, J., & Hamilton, K. L. (2004). Dietary antioxidants and exercise. J Sports Science, 22(1), 81-94.