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Dietary Antioxidants as Modifiers of Physiologic Adaptations to Exercise

MANKOWSKI, ROBERT T.1,2; ANTON, STEPHEN D.1; BUFORD, THOMAS W.1; LEEUWENBURGH, CHRISTIAAN1

Medicine & Science in Sports & Exercise: September 2015 - Volume 47 - Issue 9 - p 1857–1868
doi: 10.1249/MSS.0000000000000620
APPLIED SCIENCES
Free

Introduction Adaptive responses to exercise training (ET) are crucial in maintaining physiologic homeostasis and health span. Exercise-induced aerobic bioenergetic reactions in the mitochondria and cytosol increase production of reactive oxygen species, where excess of reactive oxygen species can be scavenged by enzymatic and nonenzymatic antioxidants (AO) to protect against deleterious oxidative stress. Free radicals, however, have recently been recognized as crucial signaling agents that promote adaptive mechanisms to ET, such as mitochondrial biogenesis, AO enzyme activity defense system upregulation, insulin sensitivity, and glucose uptake in the skeletal muscle. Commonly used nonenzymatic AO supplements, such as vitamins C and E, α-lipoic acid, and polyphenols, in combination with ET, have been proposed as ways to prevent exercise-induced oxidative stress and hence improve adaptation responses to endurance training.

Methods During the PubMed search, we selected studies that examined and compared ET effects with and without administration of commonly used AO supplements.

Results Preclinical and clinical studies to date have shown inconsistent results indicating either positive or negative effects of endurance training combined with different blends of AO supplements (mostly vitamins C and E and α-lipoic acid) on redox status, mitochondrial biogenesis pathways, and insulin sensitivity. Preclinical reports on ET combined with resveratrol, however, have shown consistent positive effects on exercise performance, mitochondrial biogenesis, and insulin sensitivity, with clinical trials reporting mixed effects. Relevant clinical studies have been few and have used inconsistent results and methodology (types of compounds, combinations, and supplementation time).

Conclusions The future studies should investigate the effects of specific AO and other popular supplements, such as α-lipoic acid and resveratrol, on training effects in humans. Of particular importance are older adults who may be at higher risk of age-related increased oxidative stress, an impaired AO enzyme defense system, and comorbidities such as hypertension, insulin resistance, and diabetes.

1Department of Aging and Geriatric Research, Institute on Aging, University of Florida, Gainesville, FL; and 2Department of Rehabilitation Medicine, Erasmus University Medical Centre, Rotterdam, THE NETHERLANDS

Address for correspondence: Christiaan Leeuwenburgh, Ph.D., Department of Aging and Geriatric Research, Institute on Aging, University of Florida, Gainesville, FL, 32611; E-mail: cleeuwen@ufl.edu.

Submitted for publication September 2014.

Accepted for publication January 2015.

Exercise training (ET) is highly recommended by health professionals for its many health benefits, including improved aerobic capacity, muscle strength, maximal oxygen uptake (V˙O2max), and overall physical condition (15). These effects are induced by adaptive responses to regular training, including improved insulin sensitivity and glucose uptake (57), improved efficiency of enzymatic antioxidant (AO) defense system (2), and increased mitochondrial biogenesis (51). Exercise-induced reactive oxygen species (ROS) are one of the signaling agents for inducing these biologic exercise-training adaptations (23). In preclinical models, improved efficiency of the enzymatic AO defense system by regular exercise protects cells against oxidative damage and maintains physiologic homeostasis (51).

Although exercise-induced ROS production is an important signaling pathway to induce biologic adaptations to training, ROS over production could also have a deleterious effect on cells and tissues, i.e., lipid and protein peroxidation (70). Therefore, some experts suggested consuming more dietary AO and AO-containing supplements to mitigate the ROS production that can cause excess oxidative stress during and after exercise (9,36,47,65). The belief that dietary supplements are helpful, or at least safe, when used in conjunction with an exercise program, however, has recently been questioned. For example, a recent study of Ristow et al. (53) found that supplementation with vitamin C (1000 mg·d−1) and E (400 IU·d−1) blunted some of the beneficial effects of exercise, such as improved insulin sensitivity, mitochondrial biogenesis level, and AO enzyme activity, in 19 untrained and 20 pretrained healthy young individuals and that exercise alone produced a better outcome. In contrast with the findings of Ristow et al. (53), previous studies have shown no blunting effects of AO supplementation on changes in aerobic capacity (V˙O2max) (16,74), mitochondrial biogenesis (74), and insulin sensitivity (74). At present, it is unclear whether AO supplements enhance or attenuate ET adaptive biologic responses in either healthy adults or lower-functioning older adults. The purpose of this article, therefore, was to review relevant studies that have examined the effects of exercise alone and combined with AO supplementation on basic training adaptations (redox status, mitochondrial biogenesis, and glucose metabolism) in both animals and humans.

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LITERATURE SEARCH

Searching PubMed for manuscripts reporting effects of AO supplements on biologic adaptation mechanisms to ET, we used combinations of the following keywords: exercise training, antioxidants, ROS signaling, vitamins, animal studies, clinical studies, resveratrol, redox status, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), oxidative stress, ROS, mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), metabolism, glucose, insulin, and insulin resistance. The goal of this literature search was to find relevant publications that will improve our understanding of the beneficial, neutral, or adverse effects of AO supplements on biologic adaptation responses in combination with endurance ET. From these articles, we selected studies that examined and compared ET effects with and without administration of commonly used AO supplements (vitamins C and E, α-lipoic acid, coenzyme-Q10, carotene, resveratrol). Controversy around biologic pathways of mitochondrial biogenesis, enzymatic AO activity, and glucose metabolism narrowed our search to only those studies that investigated an effect of ET combined with nonenzymatic AO and training alone on adaptation response to exercise. Therefore, we included all available key markers of redox status (cytosolic superoxide dismutase (SOD1), mitochondrial superoxide dismutase (SOD2), GPx, and CAT), mitochondrial biogenesis (PGC-1α), and glucose metabolism (adenosine monophosphate (AMP)-activated protein kinase (AMPK), glucose transporter 4 (GLUT4), and insulin sensitivity). Using these criteria, we identified only a few preclinical and clinical studies. We therefore included all AO supplement compounds and combinations, endurance ET duration and types, and animal and human models. The key criterion for article inclusion was a comparison between endurance ET alone and ET combined with AO supplementation. According to these criteria, 24 studies were included.

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NORMAL ADAPTATIONS OF AO ENZYMES, MITOCHONDRIAL BIOGENESIS, AND BROAD METABOLISM TO ET

Basic biologic mechanisms during exercise

ROS, within physiologic concentration, are important signaling molecules that regulate growth, proliferation, and differentiation and are responsible for some key adaptations to ET at the tissue and cellular levels; for example, AO enzyme regulation (2,31), mitochondrial biogenesis (51), and skeletal muscle hypertrophy (20).

During exercise, oxidative homeostasis is maintained by a network of AO defense mechanisms capable of producing other less reactive species or neutralizing reactive oxygen metabolites; that is, SOD, GPx, CAT, and thioredoxin reductase. SOD, for instance, promotes the dismutation of superoxide radicals (O2 •−) and forms hydrogen peroxide and oxygen. GPx uses glutathione (GSH) as a reducing equivalent for hydrogen peroxide (H2O2) to form oxidized GSH and water in the mitochondria and cytosol. In addition, CAT converts H2O2 to water and oxygen (47). In vitro studies showed that ROS (formation induced by the prooxidant herbicide paraquat) induce upregulation of the AO enzymes (SOD, GPx, and CAT) activity in myotubes (12). This mechanism maintains the oxidant–AO homeostasis during a skeletal muscle contraction in animal models and humans (34,50,62).

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Adaptation of enzymatic AO mechanisms to ET

Because prolonged exercise results in an increased production of oxidants in skeletal muscle and hence regular activation of enzymatic AO-using mechanisms, endurance ET induces adaptations resulting in upregulation of AO enzyme activity in skeletal muscle, i.e., SOD1, SOD2, GPx, and CAT (18,24,26,27,31,33,48). Endurance ET increases total SOD activity in highly oxidative Type I (the soleus) and IIA (red gastrocnemius) skeletal muscle fibers (48). Longer and more intensive endurance training promotes a greater increase in both cytosolic and mitochondrial GPx activity in oxidative skeletal muscle (Type I and IIa) fibers. Endurance training also upregulates CAT activity in the peroxisomes and mitochondria in highly oxidative muscles (48).

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Exercise-induced oxidative stress and the mitochondrial biogenesis mechanism

Endurance training does not result in parallel increases in both oxidant and AO enzyme activity (22). The AO enzyme activity of SOD, GPx, and CAT generally increases and ROS concentrations decline during normal ET (48). The mismatch seems to have an important beneficial role in ET adaptations; for example, mitochondrial biogenesis (15)/mitohormesis (53). ROS stimulate the mitochondrial biogenesis cascade in response to endurance ET [i.e., chronic muscle contractions (15)]. The newly formed mitochondria are known to be highly efficient and to produce fewer ROS for the same amount of produced adenosine triphosphate (43). Regular ET increases expression of proteins involved in mitochondrial biogenesis [i.e., PGC-1α, nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM) (Fig. 1)]. PGC-1α is an important transcriptional coactivator of nuclear genes encoding mitochondrial proteins, whereas TFAM regulates the expression of mitochondrial DNA (58). For example, expression of PGC-1α in skeletal muscle was significantly increased after 4 wk of endurance ET (53), indicating a skeletal muscle contraction-stimulated mechanism of mitochondrial biogenesis. Mitochondria are also one of the main sources of ROS, which are products of oxidative lipid and glucose metabolism during muscle contraction (53). However, the mitochondria are not the only sources of ROS during muscle contraction. For example, it has recently been shown that muscle contraction increases superoxide activity in cytosol, with a delayed increase in mitochondria. Therefore, it has been proposed that nicotinamide adenine dinucleotide phosphate oxidases are the potential sources for superoxide generation (46). Accordingly, ROS production (level of H2O2) was previously shown to increase in isolated mitochondria after acute muscle contraction in comparison with rested skeletal muscle biopsy sample (69).

Skeletal muscle contractions at high intensity increase the AMP/adenosine triphosphate ratio and the Ca2+ flux, thus causing upregulation of the gene expression and posttranslational modification of PGC-1α by the activation of AMPK, Ca2+/calmodulin-dependent kinase, and calcineurin A. Coactivation of PGC-1α activates NRF-1 and -2, which promote the expression of TFAM that directly stimulates mitochondrial DNA replication and transcription (28,45). Therefore, it consequently enhances mitochondrial biogenesis, which results in greater oxygen consumption (28).

FIGURE 1

FIGURE 1

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Exercise-induced ROS production as a signaling pathway in insulin sensitivity

Endurance ET has been shown to improve insulin sensitivity and enhance both insulin-stimulated and non–insulin-mediated glucose uptake in skeletal muscle (74). The exercise-induced enhancement in insulin-stimulated glucose disposal by skeletal muscle occurs as a result of increased protein expression of hexokinase 2 and GLUT4 (74). Muscle contraction-stimulated AMPK plays a central role in increased expression of GLUT4 and, hence, the regulation of glucose homeostasis in response to exercise. A muscle contraction increase in AMPK activity has been correlated with GLUT4 translocation and also with noninsulin glucose transport in skeletal muscle (74). Moreover, evidence indicates that exercise-induced reactive oxygen and nitrogen species (RONS) production plays an important role in regulating signaling pathways. Nitric oxide, essential for the formation of reactive nitrogen species, therefore acts as a stimulator for exercise-mediated skeletal muscle glucose uptake, showing a possible mechanism of enhanced insulin sensitivity in response to ET (74). As mentioned earlier, the muscle contraction cascade leads to a RONS-stimulated increase in expression of PGC-1α, which is an insulin sensitivity regulator (38). The latter signaling role of RONS emphasizes its importance in insulin-sensitizing mechanisms and glycemic control (53).

The current section shows the crucial role of ROS and RONS in basic adaptation mechanisms to ET. Although AO supplements may optimize the training effects by protecting against exercise-induced ROS overproduction, overdosed supplementation may impair ET’s beneficial adaptation effects.

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DIETARY AO: DAILY USAGE AND SUPPLEMENTATION

Dietary AO supplements, such as vitamins, α-lipoic acid, coenzyme-Q10, and resveratrol, are commonly used by more than half of the adults in the United States to maintain health and extend life span. Vitamin C and E supplements are the most commonly used and combined dietary supplements among older adults (65–74 yr in age) (49).

The water-soluble ascorbic acid has been suggested as a very effective donor AO (10). Moreover, the fat-soluble vitamin E (mostly α-tocopherol) as an AO can scavenge lipid radicals (68,71). Oxidized vitamin E can be transformed again to an unoxidized form by other soluble AO such as vitamin C. Therefore, that mechanism prevents vitamin E radicals from accumulating and inducing excess lipid peroxidation. The combination of vitamins C and E supplements, therefore, is most often used to potentially prevent oxidative stress and has been speculated to slow down the aging processes (68,72).

According to dietary reference intakes (tolerable upper intake levels), up to 2000 and 1000 mg of vitamins C and E, respectively, were established as the maximum levels of daily nutrient intake that are likely to pose no risk of adverse effects (39). Some preclinical studies have shown that high doses of vitamins C and E may even have prooxidative properties and increase deleterious oxidative stress (29,44). For example, in some cases, increased levels of oxidative stress led to a lens impairment that might have contributed to developed age-related cataract (75). Supplementation of diets with smaller doses (500 mg·d−1 of vitamin C), however, resulted in a significant increase in ascorbate levels in the plasma and, hence, decreased oxidative stress compared with the placebo (6).

Although even smaller doses of AO may lead to decreased ROS production, it is unknown whether decreased levels of free radicals may impair ROS-driven adaptations to ET; for example, enzymatic AO activity, mitochondrial biogenesis, and upregulated glucose metabolism. To our knowledge, there is not enough information on safe and effective dosing and interaction of vitamins and other supplements with ET in clinical studies.

Increased oxidative stress may also be deleterious in the aging process and, therefore, influence cognitive function. There is evidence that AO supplements may protect or improve cognitive function in adults age 65 yr and older (19). Supplementation with multivitamins and vitamins C, E, and β-carotene, for example, was suggested to protect the brain from oxidative damage and delay onset of cognitive decline (11,35). Results from a large, randomized, placebo-controlled trial, however, show that daily multivitamin supplementation had no benefit on delaying cognitive decline in adults age 65 yr and older after more than a decade of treatment intervention and follow-up (19). Lin et al. (35) found that none of the included trials reported any benefit from supplements on cognitive function in subjects age 69 to 95 yr with mild-to-moderate dementia. Impairments of cognitive function associated with intake of AO supplements are not reported in older adults. Future clinical studies will aim to investigate the potentially beneficial effects of AO supplements on cognitive function in nutrient-deficient older adults.

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Is there evidence that AO supplementation can improve or blunt beneficial exercise effects in animals and humans?

Undoubtedly, the damaging effects of excess ROS concentrations may include decreased muscular functionality, histologic changes, and muscular soreness and may attenuate exercise performance (38). This has been the rationale for consuming large quantities of nonenzymatic AO supplements; for example, vitamins C and E and α-lipoic acid. It also has led to research into whether nonenzymatic AO supplementation could prevent ROS’ damaging effects during exercise and thereby enhance endurance exercise performance (38) in animals and humans. In contrast to the initial protective hypothesis, preclinical studies and some recent human studies have reported controversial results on the blunting effect of nonenzymatic AO supplementation on exercise endurance training (73). Our focus will be mainly on enzymes and proteins that regulate redox biology (SOD, GPx, and CAT) and metabolism (GLUT4 and PGC-1α). We included in vivo animal and human studies on the effect of ET combined with nonenzymatic AO only in skeletal muscle.

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ET AND AO SUPPLEMENTS IN PRECLINICAL STUDIES

Redox status

ET alone induces upregulation of the main AO enzymes activities (SOD, GPx, and CAT) in an animal model in comparison with that in untrained animals. Table 1 contains preclinical studies of the effect of ET combined with AO supplementation [i.e., vitamins C and E and α-lipoic acid (1,16,23,31,37,64)]. The results showed either no additional (23,31,32,54,64) or a blunting effect (16,37) on the main AO enzyme activities.

TABLE 1

TABLE 1

Authors suggested that the effect of ET combined with AO may depend on the dosage, combination, and duration of AO supplementation and the type of ET (1). Mostly used supplement combinations were vitamins C and E (23,31,54) but also vitamin C and α-lipoic acid (64) and vitamin C alone (16,37). Interestingly, the dosages between those studies that reported no or a blunting effect did not differ. Composition of AO supplementation may also have a different AO potential, where the induced effect can be different; for example, between specific combinations and individual use (1). For example, α-lipoic acid increases vitamin E uptake in the skeletal muscle that can amplify the overall AO effect (1). The studies that reported no additional effect of AO used a combination of vitamins E and C/α-lipoic acid (23,31,64). Remarkably, the results of Meier et al. (37) and Gomez-Cabrera et al. (16) on a blunting effect of AO on redox status used vitamin C supplementation alone. According to results of Gomez-Cabrera et al. (16), vitamin C supplementation combined with ET can also impair redox status in rats. The supplementation durations differed between the studies, but this does not seem to be a key factor in blunted expression of SOD and GPx, as studies showing no effect used longer, alike, or shorter periods (23,31,54,64).

The reported significant reduction of AO enzyme activities does not seem to be induced by the duration or dosage of supplementation and training modalities. The only common factor of these two studies (Meier et al. (37) and Gomez-Cabrera et al. (16) out of the six listed in Table 1 (preclinical studies) is that in these experiments, supplementation with vitamin C alone was used in comparison with the other reported studies. Meier et al. (37) combined coenzyme Q10 and 1% N-acetylcysteine with vitamin C supplementation. However, it is unknown whether this combination had an additional blunting effect in comparison with the effect of vitamin C alone (37). This warrants future studies on the effect of AO supplementation using various clamped dosages, intervention durations, and training modalities. Future studies will improve our understanding of the supplement combinations and its effect on training-induced redox status changes.

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Mitochondrial biogenesis mechanism in response to ET combined with AO supplementation

Mitochondrial biogenesis is the essential adaptive response mechanism to endurance training, and mitochondrial content in muscle is a crucial determinant of endurance capacity (1,51). Recent preclinical studies have shown either no additional (1,23,64) or a blunting effect of ET + AO combination on protein expression of PGC-1α (16,37). Expression of PGC-1α was blunted in studies where vitamin C supplementation alone was combined with endurance ET in animals. Gomez-Cabrera et al. (16) suggested that vitamin C supplementation during endurance training blunts one of the mitochondrial biogenesis paths [i.e., PGC-1α–NRF-1– TFAM–cytochrome C (16)]. In addition, endurance training combined with vitamin C supplementation in rats blunted an improvement in running time in comparison with training alone (26.5% versus 186.7%, respectively), whereas there was no difference in V˙O2max (16). This is in agreement with the statement that endurance capacity depends on mitochondrial content in skeletal muscle and that V˙O2max is also dependent on cardiovascular training adaptations (16). However, Meier et al. (37) reported no differences in running times and found no differences in the peak power exercise tests performed at the end of the training period, in accordance with Gomez-Cabrera (16).

Moderate ROS levels are crucial for signaling pathways of mitochondrial biogenesis (1,37). Decreased expression of PGC-1α, therefore, is associated with reduced ROS-stimulated mitochondrial biogenesis. Supplementation with vitamin C decreased ROS levels, preventing enzymatic AO activity (37). Moreover, the studies of Meier et al. (37) and Gomez-Cabrera (16) are in agreement with the statement associating blunted expression of PGC-1α with decreased activity of AO enzymes (SOD, GPx, CAT), the primary endogenic AO defense system.

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Metabolic response to ET combined with AO supplementation in animal skeletal muscle

Increased expression of GLUT4 is one of major adaptive responses to endurance exercise in skeletal muscle (23). In addition, studies on endurance training adaptations have shown that expression of GLUT4 is also sensitive to redox (37). Mitochondrial biogenesis and upregulated expression of GLUT4 are mediated by the PGC-1α protein, which increases in response to acute and endurance ET (37,51).

Although studies on ET combined with AO supplements showed inconsistent results regarding redox status and mitochondrial biogenesis pathway, studies on the metabolic response show no difference in GLUT4 expression in response to ET with or without administered AO.

Only two studies investigated both expressions of PGC-1α and GLUT4 in response to ET combined with AO supplements. Meier et al. (37) found blunted PGC-1α expression and no effect on GLUT4 expression. On the other hand, Higashida et al. (23) reported no effect of the ET + AO combination on expression of PGC-1α and GLUT4.

Taken together, animal studies have shown consistent results regarding the upregulating effect of ET alone on adaptive mitochondrial biogenesis and insulin sensitivity and glycemic regulation. Conversely, results on ET + AO were equivocal, and its potential suppressing effect on ET may depend on the dose, type of AO composition, and length of time.

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ET COMBINED WITH ADMINISTRATION OF AO SUPPLEMENTS IN HEALTHY HUMANS

Redox status

Recent studies have addressed the effects of AO supplementation on ET adaptations in healthy humans (4,45,53,66,74). Ristow et al. (53) and Gomez-Cabrera et al. (16) have reported recently that AO supplementation can decrease training efficiency and prevents specific cellular adaptations of ET in healthy humans; for example, mitochondrial biogenesis. Recent clinical trials suggest that various AO that directly inhibit ROS production may ameliorate the benefits of exercise that depend on ROS signaling (16,53) or have no different effect from ET alone (66,73).

In Table 1 (clinical studies), we present relevant double-blind placebo-controlled studies that investigated enzymatic AO defense activity during endurance ET combined with vitamin C and E supplementation in young healthy adults.

Ristow et al. (53) have studied the effect of a 4-wk endurance training regimen combined with vitamin supplementation or placebo on training adaptation in 19 untrained and 20 pretrained healthy men. They reported a significant effect of vitamin C (1000 g) and E (400 IU) supplementation in blocking ET-induced expression of AO enzyme mRNA (SOD1 and GPx1) for the entire cohort of trained and untrained subjects in comparison with the no-supplementation groups (53). The findings are in agreement with the study results of Gomez-Cabrera et al. (16) and Braakhuis et al. (4), where activity of SOD, GPx, and CAT (4) decreased in response to 8 (16) and 9 wk (4) of endurance training combined with AO in untrained and trained subjects, respectively. In response to endurance and eccentric training in combination with vitamin C and E supplementation, there was no change in CAT activity in comparison with that in placebo (53,66). These results seem to indicate consistently that consumption of these amounts of vitamin C and E supplements blunts SOD and GPx activities in humans (4). Therefore, this may be blocking exercise-dependent production of the ROS (4,16) essential for hormetic stimulation of adaptive mechanisms to ET; for example, the PGC-1α pathway of mitochondrial biogenesis. Variability in levels of significance may be related to training type and duration.

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Mitochondrial biogenesis

Available study results on the effects of endurance ET with vitamin C and E supplementation on PGC-1α protein expression, the mitochondrial biogenesis coactivator, have been presented (Table 2). Paulsen et al. (45) have shown that vitamin C and E supplementation blunted any rise in muscle cytosolic PGC-1α levels during an 11-wk endurance ET program. By contrast, PGC-1α mRNA increased only in the vitamin C and E supplementation group, and nuclear PGC-1α protein levels were unchanged in both groups. The authors explain that muscle biopsies were collected 2–4 d after the last training session, and they reflect no immediate activation, nuclear translocation of PGC-1α, or gene expression during exercise (45). Yfanti et al. have shown no effect of either the training or the supplementation on the basal mRNA expression of PGC-1α (73). Ristow et al. (53) reported that an exercise-related induction of PGC-1α expression in skeletal muscle was strongly blunted after 4 wk of ET in comparison with the non-AO group. These study results coincide with the opinion that prolonged ET (4–11 wk) combined with vitamin C and E supplementation blunt ROS-stimulated cellular primary pathways of mitochondrial biogenesis that seem to block an increase in exercise performance. Yfanti et al. (74), who observed no increase in PGC-1α expression, speculate that the result may be induced by different training modalities and the applied dose of vitamin C of 500 versus 1000 mg in the rest of the relevant studies (16,45,53).

TABLE 2

TABLE 2

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Metabolic response to ET combined with AO supplements

Exercise endurance training has been shown to improve not only exercise performance but also other health-related functions, such as muscular glucose uptake, insulin sensitivity maintenance, and insulin resistance improvement (53). Animal studies have shown that overexpression of skeletal muscle PGC-1α increases insulin-stimulated glucose disposal in both healthy and insulin-resistant rats. The insulin-sensitizing effects of endurance ET seem to be blunted by decreased ROS production induced by vitamin C and E supplementation (53). Ristow et al. (53) have shown a significant effect of vitamin C and E supplementation on the blockage of an ET-induced improvement of insulin sensitivity, i.e., decreased expression of PGC-1α. It was determined by glucose infusion rates (P < 0.001) in comparison with placebo (Table 3). Although this is controversial and has not been conducted in other human studies, it is in line with some animal studies (64).

TABLE 3

TABLE 3

In contrast to the latter, Yfanti et al. (74) have shown that vitamin C and E supplementation before a 12-wk training program had no effect on insulin-stimulated glucose uptake in skeletal muscle in comparison with placebo. The increased insulin sensitivity was associated with corresponding increases in total protein kinase B (Akt), GLUT4, and hexokinase 2 in skeletal muscle in both supplementation and placebo groups, without significant differences (74). The discrepancy between those two studies may be dependent on the dose–response of the AO supplements, as the vitamin C dose was lower (500 mg) (73) where there was no effect. There is no sufficient scientific evidence, however, of impaired insulin sensitivity improvement in response to endurance training combined with vitamin C and E supplements. This warrants more studies on the AMPK–PGC-1–GLUT4 pathway in response to endurance ET with AO supplementation in human subjects. Future studies are important because the AO are often combined with exercise endurance in healthy and insulin-resistant subjects. Dose–response studies of vitamin C and E supplements during ET would contribute to recommendations on effective exercise performance improvements in athletic and clinical settings.

In conclusion, evidence exists in both animal and human studies that exercise-induced ROS play a crucial role in stimulating the signaling pathways for enzymatic AO activity (SOD, GPx, and CAT), mitochondrial biogenesis (expression of PGC-1α), and glucose metabolism (insulin sensitivity (GLUT4 expression) and glucose uptake). Moreover, adaptation to regular moderate ROS production during ET allows for more effective enzymatic ROS scavenging, increases mitochondrial oxidative capacity and its efficiency (new, more efficient mitochondria), and hence prevents deleterious overproduction of ROS. Study results are unclear about a potential suppressive role of AO supplements in impairing these ET-induced adaptive effects.

High consumption of AO in middle-age and older adults may impair desired goals to improve metabolic status (obesity, lipid profile, insulin resistance, poor physical condition). In addition, Higashida et al. (23) have suggested that the separate reports of Ristow et al. (53) and Gomez-Cabrera et al. (16), describing a suppressive role of AO supplements on ET, have to be treated with caution because of its methodology. On the other hand, Gomez-Cabrera et al. (17) contrast with Higashida et al. (23) Therefore, the unknown effects of supplemental composition, dose, and duration on adaptive training effects necessitate further studies to establish safe AO supplement types, doses, and composition without suppressing ET’s beneficial effects.

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RESVERATROL AS AN “ALTERNATIVE AO” AND ITS ROLE AS AN AO IN ET ADAPTATION IN PRECLINICAL AND CLINICAL STUDIES

Resveratrol is a polyphenolic and fat-soluble compound present mainly in grapes (7). To date, there have been several in vitro and preclinical (25,56,60,61) but also clinical studies investigating resveratrol’s AO features (14,41,42,52). Resveratrol has a short biologic half-life (8–14 min) (67), labile properties, and rapid metabolism and elimination. Because of its poor water solubility and instability, it converts to a less active cis form and its beneficial AO effect is not fully understood (67).

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Resveratrol as an AO and gene regulator

Resveratrol has been studied not only as an AO supplement that decreases deleterious amounts of ROS but also as a stimulant of energetic cellular sirtuin 1 (SIRT1)- and AMPK-dependent pathways (38), both important for PGC1a activation. Study results, however, are equivocal perhaps because of resveratrol’s poor bioavailability and solubility (3). There is some evidence of in vitro results showing improved availability and uptake of resveratrol by composing it chemically with liposomal carriers. Vanaja et al. (67), for example, found that liposomal forms of resveratrol improved its antioxidative properties and, hence, decreased oxidative damage in isolated leukocytes. Therefore, this could potentially improve resveratrol’s bioavailability and AO effects in preclinical and clinical studies, but further studies are needed. Despite the controversies regarding the bioavailability and delivery of resveratrol, spectacular improvements on metabolism and performance induced by resveratrol supplementation have been documented (mostly in animal studies) (21,30,40,52).

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EFFECTS OF ET COMBINED WITH RESVERATROL IN PRECLINICAL AND HUMAN STUDIES

Although several studies have focused on resveratrol’s effects on ET results in animal models (Table 4) (8,21,30,40,52), we are only aware of two studies that investigated a synergistic effect of combined ET with resveratrol supplementation in humans (14,41).

TABLE 4

TABLE 4

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Preclinical studies

Hart et al. (21) speculated that resveratrol may have induced posttraining improvements in aerobic capacity by simultaneously activating different molecular pathways related to mitochondrial function. Indeed, some authors reported improved V˙O2max and running time in response to resveratrol combined with ET (21,40). Other authors reported increased expression of PGC-1α and, hence, improved mitochondrial biogenesis (8,21). In accordance with an improved PGC-1α signaling pathway, an enhanced metabolic adaptive response was also reported by increased GLUT4 expression, insulin sensitivity, and glucose uptake (40).

In addition, two studies of the same group (Hart et al. (21) in 2014 and Hart et al. (22) in 2013) have investigated the effects of resveratrol in conjunction with ET on running distance in low-capacity runner (LCR) and high-capacity runner (HCR) rats, respectively. Interestingly, resveratrol supplementation combined with ET reduced running distance in LCR (22) and improved running distance in HCR rats (21). To explain this inconsistency, it was suggested that in some models, resveratrol supplementation induces different results in obesity-prone and obesity-resistant rats and its effects could be influenced by metabolic status (22).

Taken together, the authors speculate that these synergistic effects may manifest as a result of providing resveratrol when cellular energy demand is high but also in rats with high levels of performance. From these basic and preclinical studies, it seems that this potential additional effect of resveratrol on training effects provides the mechanistic action through which ET combined with resveratrol supplementation (REX) may be a feasible and efficacious intervention for maintaining functional status in humans.

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Human studies

Contrary to the aforementioned animal results on improved exercise performance after REX, one human study has shown a 45% larger improvement of V˙O2max in response to placebo after 8 wk of high-intensity training in comparison with resveratrol-supplemented subjects (Table 5) (14). The latter and other human study of Olesen et al. (41) consistently reported that ET combined with resveratrol supplementation had no additional effect on PGC-1α, SIRT1, and AMPK-induced energetic mechanisms as compared with a placebo group (14,41). In addition, Scribbans et al. (59) have also reported no additional effects of resveratrol supplementation on exercise performance and speculated that resveratrol supplementation may have a blunting effect on skeletal muscle gene expression of PGC-1α, SIRT1, and SOD2. Moreover, Gliemann et al. (14) have reported that resveratrol might have blunted a beneficial effect of ET on lipid profile. They have shown that REX eliminated the training effect on LDL, total cholesterol/HDL (TC/HDL) ratio, and triglycerides (TG) (14).

TABLE 5

TABLE 5

Contrary to animal study results, resveratrol did not improve exercise performance in healthy older adults. Interestingly, resveratrol has been shown to impair the observed ET-induced improvements in lipid profile. Moreover, resveratrol impaired a beneficial effect of the ET-induced improvement in mean arterial pressure (MAP) (14) and the muscle protein expression of vascular endothelial growth factor (VEGF) (13).

Given the inconsistency of existing animal data on REX and the few human studies indicating impairments in exercise performance and abolished exercise-induced lipid profile improvement following resveratrol supplementation, we suggest that this isolated human report of Gliemann et al. should not be a barrier to further investigation of resveratrol as a potential aid in improving ET effects in healthy subjects and in a clinical setting (hypertension, poor physical activity, reduced oxidative capacity) (14). Moreover, other authors are also critical bout the reported negative effects of resveratrol and have questioned the methodology and analyses of Gliemann et al. (5,63).

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CONCLUSIONS

The review investigated basic biologic adaptive mechanisms to ET in preclinical and clinical studies in response to ET combined with commonly used AO supplements. Most of the relevant animal and human studies showed neither additional nor adverse effects of ET combined with AO supplements on redox status, mitochondrial biogenesis, and glucose metabolism. Only a few animal and human studies have shown a blunting effect of ET combined with vitamin AO on adaptive responses to ET in healthy subjects. The reason for this inconsistency could possibly lie in different AO compositions, doses, duration time of supplementation, and ET modalities. In addition, the reported blunting effects of AO on training results could also be misleading by chosen methodology of study protocols. Moreover, it is difficult to speculate about adverse or positive clinical effects of resveratrol because of a narrow body of evidence and because experiments were conducted in only healthy subjects. To date, a blunting influence of AO supplementation during ET in healthy humans remains speculative. The lack of strong evidence indicating adverse and/or positive effects and the unclear methods of AO administration in combination with ET, however, warrant future studies in healthy aging populations and individuals with chronic health conditions such as sarcopenia, hypertension, and poor physical aerobic condition, for whom training adaptations are crucial for health improvement.

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Future directions

The review highlights studies on AO supplements’ adverse blunting effects on mitochondrial biogenesis pathways and suggests ROS-induced impaired signaling mechanisms. Enzymatic AO activity seems to be an efficient and effective defense against oxidative stress during ET in healthy young and middle-age adults. Therefore, future double-blinded placebo-controlled studies should focus on investigating a potential positive or negative effect of AO supplements on key ET adaptation mechanisms in older adults with deficiencies. Such studies may evaluate exercise responses for relevant biologic factors such as mitochondrial biogenesis, insulin, skeletal muscle glucose uptake, and redox status. Although speculative, adverse and/or positive effects of AO supplementation on ET results may depend on doses, compounds, combinations, and endurance training modalities. To address this hypothesis, dose–response clinical trials are needed to determine safe and training-efficient supplementation strategies combined with ET in both healthy and unhealthy older adults.

There was no funding provided during the writing of this article.

The article does not contain clinical studies and patient data. The authors declare no conflict of interest. In addition, we recognize other reports in the area that could not be cited because of journal formatting requirements.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

EXERCISE TRAINING; DIETARY ANTIOXIDANTS; MITOCHONDRIAL BIOGENESIS; REDOX STATUS; GLUCOSE METABOLISM

© 2015 American College of Sports Medicine