Antioxidants... Do they hinder our gains or not?

[NO HYPE]

I've noticed a lot of talk about reducing/not reducing inflammational response prior to and/or following workouts.

For those of us with inflammatory conditions, who regularly administer antioxidants (and who also want to continue to efficiently build muscle), it would be nice to have something to go by. Obviously inflammation is key to muscle growth, however.... to what extent? At what point does antioxidant supplementation, actually impede muscle growth?

I realize that many of these questions will go unanswered however, the more we can dig up on the subject.... the better off we'll be.



1: Am J Physiol Cell Physiol. 2004 Aug;287(2):C475-83. Epub 2004 Apr 14.

The COX-2 pathway is essential during early stages of skeletal muscle regeneration


Skeletal muscle regeneration comprises several overlapping cellular processes, including inflammation and myogenesis. Prostaglandins (PGs) may regulate muscle regeneration, because they modulate inflammation and are involved in various stages of myogenesis in vitro. PG synthesis is catalyzed by different isoforms of cyclooxygenase (COX), which are inhibited by nonsteroidal anti-inflammatory drugs. Although experiments employing nonsteroidal anti-inflammatory drugs have implicated PGs in tissue repair, how PGs regulate muscle regeneration remains unclear, and the potentially distinct roles of different COX isoforms have not been investigated. To address these questions, a localized freeze injury was induced in the tibialis anterior muscles of mice chronically treated with either a COX-1- or COX-2-selective inhibitor (SC-560 and SC-236, respectively), starting before injury. The size of regenerating myofibers was analyzed at time points up to 5 wk after injury and found to be decreased by SC-236 and in COX-2?/? muscles, but unaffected by SC-560. In contrast, SC-236 had no effect on myofiber growth when administered starting 7 days after injury. The attenuation of myofiber growth by SC-236 treatment and in COX-2?/? muscles is associated with decreases in the number of myoblasts and intramuscular inflammatory cells at early times after injury. Together, these data suggest that COX-2-dependent PG synthesis is required during early stages of muscle regeneration and thus raise caution about the use of COX-2-selective inhibitors in patients with muscle injury or disease. http://www.ncbi.nlm.nih.gov/sites/entrez



1: Am J Physiol Cell Physiol. 2006 Jun;290(6):C1651-9. Epub 2006 Feb 8. Links

The COX-2 pathway regulates growth of atrophied muscle via multiple mechanisms.


Loss of muscle mass occurs with disease, injury, aging, and inactivity. Restoration of normal muscle mass depends on myofiber growth, the regulation of which is incompletely understood. Cyclooxygenase (COX)-2 is one of two isoforms of COX that catalyzes the synthesis of prostaglandins, paracrine hormones that regulate diverse physiological and pathophysiological processes. Previously, we demonstrated that the COX-2 pathway regulates early stages of myofiber growth during muscle regeneration. However, whether the COX-2 pathway plays a common role in adult myofiber growth or functions specifically during muscle regeneration is unknown. Therefore, we examined the role of COX-2 during myofiber growth following atrophy in mice. Muscle atrophy was induced by hindlimb suspension (HS) for 2 wk, followed by a reloading period, during which mice were treated with either the COX-2-selective inhibitor SC-236 (6 mg x kg(-1) x day(-1)) or vehicle. COX-2 protein was expressed and SC-236 attenuated myofiber growth during reloading in both soleus and plantaris muscles. Attenuated myofiber growth in the soleus was associated with both decreased myonuclear addition and decreased inflammation, whereas neither of these processes mediated the effects of SC-236 on plantaris growth. In addition, COX-2(-/-) satellite cells exhibited impaired activation/proliferation in vitro, suggesting direct regulation of muscle cell activity by COX-2. Together, these data suggest that the COX-2 pathway plays a common regulatory role during various types of muscle growth via multiple mechanisms. http://www.ncbi.nlm.nih.gov/sites/en...RVAbstractPlus

[DRP7]

I don't have an answer to this but I would just throw in that not all "antioxadnts" per se do inhibit the COX-2 pathway nor are all COX-2 inhibitors necessarily antioxidants.
however, especially when speaking about popular herbal substances (catechins etc), there is surely a large overlap between those two groups.

last year someone posted a study about how more than 500 mg of Vitamin C hampered the performance gains during a training period (I think runners have been investigated). there have been a lot of hypotheses how and why this could happen.
Well, Vit. C has been shown to have inhibitory as well as facilitatory effects on COX, dependend on the metabolic context and other drugs that are being applied (e.g. it supports the COX-2 inhibition of aspirin and supresses COX-2 expression in leukemia cells but elevates COX-2 in murine macro****es and placenta). So, if COX-2 inhibition is the reason why Vitamin C may have shwon negative effects on training-induced performance gains, then we might have a case here.
on the other side, we don't exactely know whether Vit-C actually inhibit COX-2 in muscle cells after training. possibly it does. but it is possible as well that it elevates COX-2 (but rather unlikely) and it is very possible that it does not do anything with COX-2 at all.

anyways, there is a second line of reasoning that does not relate to COX-2 at all but to the mere ROS-scavenging effects of Vit. C:
The presence of Vit. C, especially at higher doses could lead to a decreased antioxidative response of tissues to training-induced oxidative stress. studies in rodents have shown that long-tern supplementation with Vit C. decreases the levels of antioxidative enzymes (gutathione-enzymes etc.). moreover, other studies have shown that physical exercise / training dramatically improves the resistance of tissues against hypoxemia / ischemia and ischemia-related excess of oxidative stress. where does this resisitance comes from? most probably from an upregulated antioxidative capacity due to active antioxidative enzymes.
It could now be hypothesized that the presence of high / supraphysiological levels of Vit. C or any other exogenous antioxidant may decrease the need to upregulate the antioxidative enzymatic machinery as a response to training-induced oxidative damage. and this, ladies and gentlemen, could have bad consequences because - as we all know - the antioxidative efficiency of body's own antioxidative enzymes is waaayyys superior to any exogenous antioxidant.

It can be thus hypothesized, that it can possibly be better to let the body itself fight with the training-induced oxidative stress in order to develop the best possible antioxidative repsonse and resistance than to fill the body with exogenous antioxidants that will protect it a little from training induced ROS but that possibly will hamper the body's own (and superior) response to this ROS.

everything I presented is based on speculation and does not really answer your questions. but nonetheless, something for the "warming-up", so to say

[War Machine]

So the multi I take with my PWO shake that has extra anti-oxidants should be skipped?

I usually take it when I wake up and PWO. I thought process has been those are the two times the body wants vitamins/minerals/nutrients and are more apt to assimulate them, but if the antioxidants hinder more than help...

[DRP7]

So the multi I take with my PWO shake that has extra anti-oxidants should be skipped?

I usually take it when I wake up and PWO. I thought process has been those are the two times the body wants vitamins/minerals/nutrients and are more apt to assimulate them, but if the antioxidants hinder more than help...

no, don't skip it because of what you have read so far int his thread. this has been pure speculation and theorizing. the effects of antioxidant supplementation on training performance have not been systematically investigated so far. and please remember that different antioxidants can have very different properties.

[dannov]

I'd be more worried about the quality of the supplement that you are taking. Anything stacking antis with a multivitamin probably has lower-than-effective quantities of said antioxidant ingredients in its formula. Antioxcene is a great one to take.

[RB12]

I'd be more worried about the quality of the supplement that you are taking. Anything stacking antis with a multivitamin probably has lower-than-effective quantities of said antioxidant ingredients in its formula. Antioxcene is a great one to take.

get this out of here pimp your crap elsewhere

[in10city]

The degree of inflammation required to produce a positive response and the point at which it becomes negative are important markers.

I'm sure many people take it beyond the point of diminishing returns. Furthermore, many of the supplements (like the enzyme products) are just not potent enough to shut the process off completely, but rather serve to attenuate it.

As with so many things, it appears to be a balancing act between the production of inflammation and the use of supplements at the right times to bring inflammation, if in excess, down to a positive level.

BTW, if you haven't seen this - Winning With The Enzymatic Edge - besides being an good read, there are 60+ references at the end to dig into ...

[GeneGnomeX]

Here is how I understand it, highly simplified, one example pathway.

Contraction induced ROS is at least partly responsible for an increase in intracellular calcium influx. This begins the adaptation cascade.

In endurance exercise, the flux is low and sustained and activates calcineurin which dephosphorylates NFAT which can then enter the nucleus. This then promotes expressions that promote slow fiber conversion by binding DNA to MEF2 etc.

In resistance exercise, the calcium influx is high and irregular, not sufficient to activate calcineurin. NFAT stays phosphorylated and expressions to promote fast fibers are started.

Still trying to map this out on paper, some of these pathways aren't very conclusive

[dannov]

get this out of here pimp your crap elsewhere

I'm not a rep you douche, merely recommending what I use. I personally like the formula in this product.

[GeneGnomeX]

I'm not a rep you douche, merely recommending what I use. I personally like the formula in this product.

This is the science section

[dannov]

Sorry, I clicked the thread off another link and didn't pay attention to which forum it was in. Won't happen again.

[Progressive8]

wow interesting....im a HUGE vitamin C fan, at times i take up to 6000mg's from just supps alone(but i usually take about half that daily) and my gains have always been slow accept when i was a newb but....i would say my gains have been a little better since i have been taking alot of vit C. It dosent really seem to speed recovery for me but it does seem to help my immune system, keeping me from getting sick, which in turn, keeps me from missing work out's do to illness. So whether it's reducing oxidative stress,weekening my own ROS protection systems, or even reducing inflamation thus decreasing the anabolic response to training, the immune system boosting is one varible to consider when discussing vitamin C. I wouldnt be so worried about the reduction in inflamtion though, because EFA's/Fish oil also reduces inflamation, but most people consider this a staple supplement. Further more, many bodybuilding foods contain many anti-inflamtory fats, vitamins, and minerals(tuna is a good example) and i doubt eating tuna hinders gains.

[GeneGnomeX]

wow interesting....im a HUGE vitamin C fan, at times i take up to 6000mg's from just supps alone(but i usually take about half that daily) and my gains have always been slow accept when i was a newb but....i would say my gains have been a little better since i have been taking alot of vit C. It dosent really seem to speed recovery for me but it does seem to help my immune system, keeping me from getting sick, which in turn, keeps me from missing work out's do to illness. So whether it's reducing oxidative stress,weekening my own ROS protection systems, or even reducing inflamation thus decreasing the anabolic response to training, the immune system boosting is one varible to consider when discussing vitamin C. I wouldnt be so worried about the reduction in inflamtion though, because EFA's/Fish oil also reduces inflamation, but most people consider this a staple supplement. Further more, many bodybuilding foods contain many anti-inflamtory fats, vitamins, and minerals(tuna is a good example) and i doubt eating tuna hinders gains.

An imbalance of fat sources increases inflammation. Taking fish oil is an attempt to get yourself to "normal," since western diets are generally void of balance. There is actual research IIRC on fish oil post exercise reducing protein synthesis (?) and this makes sense by its MOA.

We're not talking foods here, it is single, potent antioxidants instead of an intake of a balanced variety, each which have varying potency and slightly different effect on gene expressions. And, focusing mostly around workouts. Comparing tuna consumption to antioxidant supplementation is illogical for a number of reasons and has no relevance here.

It might be necessary to take something like extra C which has been studied considerably and appears safe, since even with a well balanced diet, we have things like polution and stressful jobs that might increase ROS production a bit higher than desired.

Another thing to consider that I hadn't until recently is the effects of the metabolites of these single antiox, quercetin for example has some negative stuff recently, here is one:

1: Toxicol Appl Pharmacol. 2007 Jul 1;222(1):89-96. Epub 2007 Apr 24.
Links
The quercetin paradox.
Boots AW, Li H, Schins RP, Duffin R, Heemskerk JW, Bast A, Haenen GR.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. a.boots@farmaco.unimaas.nl

Free radical scavenging antioxidants, such as quercetin, are chemically converted into oxidation products when they protect against free radicals. The main oxidation product of quercetin, however, displays a high reactivity towards thiols, which can lead to the loss of protein function. The quercetin paradox is that in the process of offering protection, quercetin is converted into a potential toxic product. In the present study, this paradox is evaluated using rat lung epithelial (RLE) cells. It was found that quercetin efficiently protects against H(2)O(2)-induced DNA damage in RLE cells, but this damage is swapped for a reduction in GSH level, an increase in LDH leakage as well as an increase of the cytosolic free calcium concentration. To our knowledge, this is the first study that indicates that the quercetin paradox, i.e. the exchange of damage caused by quercetin and its metabolites, also occurs in living lung cells. Following depletion of GSH in the cells by BSO pre-treatment, this quercetin paradox becomes more pronounced, confirming that the formation of thiol reactive quercetin metabolites is involved in the quercetin paradox. The quercetin paradox in living cells implies that the anti-oxidant directs oxidative damage selectively to thiol arylation. Apparently, the potential toxicity of metabolites formed during the actual antioxidant activity of free radical scavengers should be considered in antioxidant supplementation.

PMID: 17537471 [PubMed - indexed for MEDLINE]

So, this needs to be taken pretty seriously. If limiting oxidative damage post exercise is something you feel works (or just for a general boost in antiox intake), I would suggest looking into superfruits, if you have ethnic grocery stores around they should have a bigger selection.

[ShadyShadow13]

guys your smart ..
so when you find the answer tell me with refernces .. for now i will keep my anti oxidants up .. especially vit C .. it rocks

[NO HYPE]

guys your smart ..
so when you find the answer tell me with refernces .. for now i will keep my anti oxidants up .. especially vit C .. it rocks

Well here's an abstract reguarding ROS and internal antioxidant mechanisms, that would lead one to believe that supplementing powerful antioxidants prior to a workout.... may not be such a good idea. Amongst other beneficial actions in the muscle, ROS appears to actually play a role in skeletal muscle contractile force.

As for myself (even though I merely maintain weight vs trying to gain it).... I've had no issues with post-workout antioxidant administration, but then again.... what would be the signs to look for anyways?

I would think that avoiding the downregulation of inflammational response untill some time AFTER the workout, would allow for the beneficial mechanisms of inflammation/ROS to elicit their actions.




1: Front Biosci. 2007 Sep 1;12:4826-38. Links

Response and adaptation of skeletal muscle to exercise--the role of reactive oxygen species.


In the last 30 years, the role of reactive oxygen species (ROS) in exercise physiology has received considerable attention. Acute physical exertion has been shown to induce an augmented generation of ROS in skeletal muscle via different mechanisms. There is evidence that ROS formation in response to vigorous physical exertion can result in oxidative stress. More recent research has revealed the important role of ROS as signaling molecules. ROS modulate contractile function in unfatigued and fatigued skeletal muscle. Furthermore, involvement of ROS in the modulation of gene expression via redox-sensitive transcription pathways represents an important regulatory mechanism, which has been suggested to be involved in the process of training adaptation. In this context, the adaptation of endogenous antioxidant systems in response to regular training reflects a potential mechanism responsible for augmented tolerance of skeletal muscle to exercise-induced stress. The present review outlines current knowledge and more recent findings in this area by focussing on major sources of ROS production, oxidative stress, tissue damage, contractile force, and redox-regulated gene expression in exercising skeletal muscle. http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum

[NO HYPE]

I've noticed a lot of talk about reducing/not reducing inflammational response prior to and/or following workouts.

For those of us with inflammatory conditions, who regularly administer antioxidants (and who also want to continue to efficiently build muscle), it would be nice to have something to go by. Obviously inflammation is key to muscle growth, however.... to what extent? At what point does antioxidant supplementation, actually impede muscle growth?

I realize that many of these questions will go unanswered however, the more we can dig up on the subject.... the better off we'll be.

If anyone can get access to this entire study.... some questions may in fact, be answered.



1: J Nutr Biochem. 2007 Jun;18(6):357-71. Epub 2006 Dec 6. Links

The influence of antioxidant supplementation on markers of inflammation and the relationship to oxidative stress after exercise.


Interest in the relationship between inflammation and oxidative stress has increased dramatically in recent years, not only within the clinical setting but also in the fields of exercise biochemistry and immunology. Inflammation and oxidative stress share a common role in the etiology of a variety of chronic diseases. During exercise, inflammation and oxidative stress are linked via muscle metabolism and muscle damage. Because oxidative stress and inflammation have traditionally been associated with fatigue and impaired recovery from exercise, research has focused on nutritional strategies aimed at reducing these effects. In this review, we have evaluated the findings of studies involving antioxidant supplementation on alterations in markers of inflammation (e.g., cytokines, C-reactive protein and cortisol). This review focuses predominantly on the role of reactive oxygen and nitrogen species generated from muscle metabolism and muscle damage during exercise and on the modulatory effects of antioxidant supplements. Furthermore, we have analyzed the influence of factors such as the dose, timing, supplementation period and bioavailability of antioxidant nutrients. http://www.ncbi.nlm.nih.gov/sites/en...ubmed_RVDocSum

[DRP7]

voila:

J Nutr Biochem. 2007 Jun;18(6):357-71. Epub 2006 Dec 6.

The influence of antioxidant supplementation on markers of inflammation and the relationship to oxidative stress after exercise
Jonathan M. Peakea, Corresponding Author Contact Information, E-mail The Corresponding Author, Katsuhiko Suzukib, c and Jeff S. Coombesa


1. Introduction

Exercise is known to have many benefits, including preventative and therapeutic effects on a variety of chronic disorders such as diabetes mellitus; dyslipidemia; hypertension; obesity; cardiovascular and pulmonary diseases; muscle, bone and joint diseases; cancer; and depression [1]. Many of these chronic disorders share a common link with chronic low-grade inflammation and overproduction of reactive oxygen and nitrogen species (RONS) [2]. Increasing evidence suggests that the health benefits of exercise are partly linked to reduced levels of inflammation and oxidative stress [3] and [4].

It is well accepted that the health benefits of exercise are enhanced by positive dietary modification. The relationship between inflammation and oxidative stress has generated interest in the benefits of antioxidant supplements in health and disease, as well as athletic performance and adaptation to training. Over the years, exercise scientists have examined the potential effect of antioxidant nutrients to counter the influence of RONS on muscle damage, muscle fatigue, lipid peroxidation and damage to cellular proteins and DNA during exercise. However, attention has more recently shifted toward the specific interaction between antioxidant nutrients, redox-sensitive signaling pathways and inflammatory responses to exercise. Evidence suggests that antioxidant supplementation may in fact attenuate some of the exercise-induced cellular signals that stimulate adaptations in vascular tissue and skeletal muscle also exists [5] and [6]. The number of studies that have investigated this issue has risen in recent years, and this has stimulated interesting debate [7], [8], [9], [10] and [11].

The aim of this review article is to collate and review the findings of studies that have examined the effects of antioxidant supplements on inflammatory responses to exercise. In the first part of this review, we have briefly discussed the mechanisms that contribute to cytokine changes during exercise. This is followed by a short discussion of the mechanisms of production of RONS during exercise, the signaling pathways that may regulate cytokine production during exercise and, more specifically, how such pathways are influenced by RONS and antioxidant nutrients. In the second half of this review, we have provided a detailed description of the findings from studies that have investigated the interaction between antioxidants, RONS and inflammation after exercise. This is followed by a discussion of the nutritional and biochemical factors that may account for the disparate findings of studies in this area, including the dose, timing and period of supplementation, in addition to the bioavailability and activity of antioxidants used in these studies. The main focus of this review is on the relatively new issue of the relationship between antioxidants and inflammatory responses to exercise. Related issues such as the influence of antioxidant supplementation on markers of muscle damage and oxidative stress have been reviewed elsewhere. Consequently, we have not addressed these issues in detail in the present review.

2. Exercise and cytokine production

A basic representation of the interactions between exercise, RONS, antioxidants and cytokines is shown in Fig. 1. Cytokine production during exercise is influenced by a number of factors [12]. Muscle glycogen breakdown and Ca2+ are two important factors that regulate cytokine production within skeletal muscle during exercise [13]. Immune cells are mobilized and activated during exercise in response to muscle damage and also via the actions of stress hormones (catecholamines, growth hormone, cortisol) that are released in response to increasing metabolic demands and core temperature during exercise [14] and [15]. Interactions between immune cells and stress hormones contribute to alterations in cytokine production [16]. Elevated core temperature during exercise can promote the leakage of endotoxins (lipopolysaccharide) across the intestinal wall into the circulation, and this may alter cytokine production [17].
Exercise-induced oxidative stress is another factor that affects cytokine production. Oxidative stress may result from oxidative reactions within skeletal muscle as well as from muscle damage [18]. RONS generated through oxidative metabolism and muscle damage can activate redox-sensitive signal transduction pathways that control cytokine production, such as those involving nuclear transcription factor κB (NF-κB), calcinuerin-nuclear factor activated T cells (NFAT) and heat shock proteins (HSPs) [19], [20], [21], [22] and [23]. During exercise, endogenous antioxidant enzymes and dietary antioxidant supplements can potentially attenuate cytokine production by directly neutralizing RONS [24] and/or inhibiting the activity of redox-sensitive signal transduction pathways [20] and [21]. Some cytokines themselves may cause production of RONS and/or the activation of NF-κB [25]. Finally, instead of acting as antioxidants in some situations, α-tocopherol and ascorbic acid may actually act as ?pro-oxidants,? thereby enhancing rather than reducing the formation of RONS [26].

3. Production of ROS and RNS during exercise

In response to electrical stimulation, cultured myotubes produce reactive oxygen species (ROS) such as superoxide anions, hydroxyl radicals and hydrogen peroxide (H2O2), as well as reactive nitrogen species (RNS) such as nitric oxide [27], [28] and [29]. Voluntary muscle contractions also stimulate the release of free radicals from muscle into the bloodstream [24], [30] and [31]. During muscle contractions, RONS may be produced as a result of aerobic metabolism and/or activation of ****ocytic cells in response to muscle damage. Within skeletal muscle, potential sources of RONS include (a) mitochondria, (b) an unidentified oxidoreductase enzyme located in the plasma membrane of fibroblasts and immune cells present within muscle, (c) xanthine oxidase produced by endothelial cells and (d) iron-catalyzed reactions [28], [32] and [33]. Although the majority of early studies investigated the potential for damaging contractile activity (eccentric exercise) to generate RONS, these reactive species are also produced in response to nondamaging contractions (concentric exercise) [27] and [28].

These findings have led to interest in researching the effects of antioxidant supplementation ? and therefore the involvement of RONS ? on changes in cytokines and other markers of inflammation (e.g., cortisol, C-reactive protein) following both eccentric and concentric exercises. Due to the greater amount of muscle damage that is typically associated with eccentric exercise, there may be differences in terms of the amount and source of RONS that are generated following eccentric versus concentric exercise. This might partially explain why antioxidant supplementation attenuates cytokine responses after some forms of exercise but not others.

[DRP7]

4. Redox regulation of cytokine production

Redox regulation of cytokine production occurs at several levels including direct effects of oxidants, modulation by antioxidants, alterations in the redox equilibrium (e.g., ratio of reducedxidized glutathione and thioredoxin) and activation of oxidant- and redox-sensitive transcription cofactors such as NF-κB [19]. Among these regulatory pathways, two studies have directly implicated ROS and NF-κB with cytokine production by muscle cells in vitro [20] and [21], while the majority of exercise studies have focused on modulation of cytokine production by antioxidants. The following sections describe the involvement of redox-sensitive transcription cofactors in the regulation of cytokine production.

4.1. NF-κB as a redox-sensitive pathway for cytokine production

The NF-κB signaling pathway is one particular redox-sensitive signaling pathway that is proposed to regulate cytokine production during exercise [20] and [21]. Exercise activates the NF-κB signaling pathway in skeletal muscle [20], [34] and [35] and lymphocytes [36]. This effect may be mediated in part by RONS [20] and [21]. Evidence in support of this concept comes from the data of two studies involving antioxidants. One study reported that in rats a 3-week diet high in α-tocopherol (500 mg/kg) attenuated the activation of NF-κB, the protein content of cytokine-induced neutrophil chemoattractant-1 (CINC-1), monocyte chemotactic protein-1 (MCP-1) and the activity of neutrophil-derived myeloperoxidase in skeletal muscle after exercise [20]. The same group also incubated myoblast cells with 100 μM d-α-tocopherol for 24 h and then exposed the cells to H2O2. d-α-tocopherol inhibited the translocation of NF-κB into the cell nucleus and the mRNA expression of CINC-1 and MCP-1 [20]. These data indicate, firstly, that RONS are involved in the activation of NF-κB and, secondly, that inhibition of NF-κB attenuates the production of cytokines in muscle cells.

In another study, myotubes exposed in vitro to H2O2 produced the cytokine interleukin (IL)-6 in a concentration-dependent manner [21]. This effect was blocked by the pretreatment of the myotubes with the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Blocking of p38 mitogen-activated protein kinase (MAPK) and NF-κB also reduced the amount of IL-6 produced when the myotubes were stimulated with H2O2. When undifferentiated myoblast cells were stimulated with tumor necrosis factor (TNF)-α, IL-6 was produced. This effect was also blocked by the glutathione precursor N-acetylcysteine (NAC) [21]. These data indicate that IL-6 is produced in muscle cells via redox-sensitive pathways that involve p38 MAPK and NF-κB.

Despite this evidence for a role of RONS and NF-κB in the production of cytokines within skeletal muscle cells, there is also evidence suggesting that RONS may not be universal messengers in the activation of NF-κB. Instead, RONS may work as second messengers to activate NF-κB [37]. The ability of RONS to activate NF-κB depends on the cell type and may be linked to the levels of antioxidants within the cells. Even within one cell type, the effects of RONS can be variable [38]. Cytokines such as TNF-α can activate NF-κB independently of RONS, and in some cases, RONS actually inhibit these effects [38]. Lastly, antioxidants (e.g., ascorbic acid, NAC and pyrrolidine diothiocarbamate) can inhibit activation of NF-κB independently of any true antioxidant mechanisms [39] and [40].

4.2. Calcineurin-NFAT as a redox-sensitive pathway for cytokine production

Another redox-sensitive signaling pathway that has been proposed to regulate cytokine production during exercise is the calcineurin-NFAT pathway [13]. Calcineurin is highly concentrated in skeletal muscle [41]. When activated by calcium, calcineurin subsequently dephosphorylates and induces the nuclear localization of the cytosolic components of NFAT. Once in the nucleus, NFAT transcription complexes bind to DNA to regulate the expression of genes involved in immune responses [42]. Indeed, the calcineurin-NFAT signaling pathway plays a key role in the synthesis of TNF-α, IL-1β, IL-6 [43], [44] and [45] and NF-κB [46]. Interaction between NFAT and the transcription factor activating protein-1 also promotes cytokine production [47].

Several studies have investigated the interaction between antioxidants, RONS and calcineurin-NFAT signaling. Pretreatment of human MRC5 fibroblast cells with 10 μM dl-α-tocopherol reduced lipid peroxidation [48] and partially prevented an increase in free intracellular Ca2+ and NFAT binding activity following exposure to ultraviolet A radiation [22]. In another study by the same group, pretreatment of human Jurkat (T lymphocyte) cell lines with 10 μM dl-α-tocopherol also attenuated the production of RONS, the rise in free intracellular Ca2+ and NFAT binding activity following exposure to copper-oxidized and monocyte-oxidized low-density lipoproteins [49]. These data indicate that the calcineurin-NFAT signaling pathway is redox sensitive. In contrast to these findings, exposure of splenic T cells from rats to xanthine/xanthine oxidase and H2O2 actually reduced the binding activity of NFAT and NF-κB [50]. This result suggests that the effect of RONS on these transcription factors may be specific to certain cell types.

To date, no studies have investigated the involvement of the calcineurin-NFAT signaling pathway in cytokine synthesis during exercise. However, Holmes et al. [51] have demonstrated that incubation of muscle with the calcium ionophore, ionomycin, at a concentration of 10 μM increased IL-6 mRNA expression and protein release. Therefore, calcium release during exercise may stimulate IL-6 production via activation of the calcineurin-NFAT signaling pathway [13]. Further research is needed to determine whether exercise-induced alterations in this pathway are modified by antioxidants and whether this influences inflammatory responses to exercise.

4.3. HSPs as redox-sensitive mediators of cytokine production

Evidence showing that HSPs play an important role in exercise-induced immune changes is increasing [12] and [52]. Heat is a stimulus for the induction of HSPs, but RONS have been directly implicated as mediators of this response [23], [53] and [54]. HSPs are induced by oxidative damage to the upstream signaling protein heat shock factor (HSF)-1 [55]. Antioxidants attenuate HSP induction in immune cells exposed to hot conditions [53] and also when immune cells are exposed directly to RONS [23]. It is unclear whether antioxidants work directly to modify HSF-1 activity or inhibit HSF-1 activation by preventing oxidative damage to HSF-1 [55]. Exercise studies are yet to confirm a link between oxidative modification of HSPs and subsequent inflammatory responses. However, antioxidants attenuate the release of HSPs into the circulation, in addition to HSP mRNA expression and protein content in skeletal muscle following exercise [23], [56] and [57]. Therefore, future research could be aimed at investigating the relationships between exercise-induced oxidative stress, induction of HSPs and cytokine production.

[DRP7]

5. Antioxidant supplements and cytokine responses to concentric exercise

Several studies have examined the efficacy of antioxidant supplements on cytokine responses to nondamaging exercise such as cycling and knee-extension exercise (Table 1). During these types of exercise, antioxidants might be expected to alter cytokine production via their effect on RONS produced from sources such as mitochondria and xanthine oxidase. Muscle damage is relatively minor following these types of exercise, and therefore, RONS produced by ****ocytic cells probably have less influence on cytokine production after cycling and knee-extension exercise.

5.1. Supplementation with vitamin C

Davison and Gleeson [58] and [59] have carried out two studies to investigate the effect of vitamin C on changes in IL-6 following 2.5 h of cycling at 60% VO2max. Acute supplementation with vitamin C during exercise did not influence changes in plasma IL-6 concentration after exercise in moderately trained males (Table 1) [58]. It should be noted in Table 1 that plasma IL-6 concentration was lower following exercise versus the placebo only when carbohydrate was combined with vitamin C. Vitamin C had no significant effect on plasma cortisol concentration after exercise. In their second study, supplementation with 1000 mg vitamin C per day for 2 weeks also had no significant effect on plasma IL-6 concentration following exercise in well-trained cyclists (Table 1) [59]. Vitamin C tended to reduce plasma cortisol concentration after exercise (P=.08). As a marker of oxidative stress, plasma malondialdehyde concentration remained unchanged after exercise. In vitro production of ROS by stimulated neutrophils decreased after exercise and was not affected by vitamin C.

5.2. Supplementation with antioxidant combinations

Vassilakopoulos et al. [60] investigated the effect of a complex antioxidant supplementation regimen on changes in the plasma concentrations and monocyte production of IL-1β, TNF-α and IL-6 after 45 min of cycling at 70% VO2max (Table 1). The study involved a crossover design. Supplementation significantly attenuated plasma cytokine concentrations, while there was no effect of exercise or supplementation on monocyte cytokine production.

Fischer et al. [61] gave physically active males a combination of 500 mg vitamin C and 400 IU RRR-α-tocopherol per day for 4 weeks before and 1 day after 3 h of two-legged knee extension exercise at 50% maximum power output. The antioxidant supplement attenuated the release of IL-6 from contracting muscle. Furthermore, the plasma concentrations of IL-6, IL-1 receptor antagonist (IL-1ra), C-reactive protein and cortisol were lower following exercise in the supplement versus the placebo group (Table 1). As evidence of a reduction in oxidative stress, the plasma concentration of F2-isoprostanes did not change significantly after exercise in the supplement group, whereas it increased significantly in the placebo group.

Hagobian et al. [62] examined the effect of antioxidant supplementation on cytokine responses to exercise at a high altitude (4800 m). Moderately trained males were given a placebo or an antioxidant supplement containing 250 mg vitamin C, 10,000 IU β-carotene, 200 IU α-tocopherol, 50 μg selenium and 15 mg zinc for 3 weeks before cycling at 55% VO2max for approximately 3 h. Supplementation did not influence changes in the plasma concentrations of IL-6 and C-reactive protein, while plasma TNF-α concentration remained unchanged following exercise.

5.3. Discussion

The results of studies by Vassilakopoulos et al. [60] and Fischer et al. [61] indicated that antioxidant supplements attenuate inflammatory responses to concentric exercise during which muscle damage and inflammation are minimal. Both of these studies used a combination of antioxidants, and it is possible that this is a more effective supplementation regimen than using single antioxidants on their own [60] and [63]. However, this concept cannot account for the findings in the study by Hagobian et al. [62].

The lack of any effect of vitamin C in the first study by Davison and Gleeson [58] could be due to the fact that participants were only given vitamin C during and not before exercise. Consequently, there was probably minimal uptake of ascorbic acid into leukocytes and muscle tissue where it might be expected to modify cytokine production. Furthermore, addition of vitamin C to the sports drink containing carbohydrate did not have any additional effect on the alterations in plasma IL-6 and cortisol concentrations after exercise [58]. One explanation for this finding is that blood glucose levels regulate changes in IL-6 and cortisol during exercise [64], while vitamin C has less effect.

Hagobian et al. [62] suggested that the negative findings in their study could have been related to the fitness level or training status of their participants. It is possible that untrained individuals may be more responsive to antioxidant supplementation than endurance-trained athletes. Some [65] and [66] but not all studies [67] and [68] indicate that endurance training improves endogenous antioxidant defenses. With the exception of the participants in the study by Vassilakopoulos et al. [60], the participants in the other studies described above were all physically active or well trained. Therefore, training status may not account for all of the variation in responsiveness to antioxidant supplementation. The magnitude of exercise-induced changes in cytokines also did not seem to influence the efficacy of antioxidant supplements.

6. Antioxidant supplements and cytokine responses following moderate- to high-intensity running of 1.5 to 2.5 h in duration

Several studies have investigated whether supplementation with vitamins C and E modifies cytokine responses to running. The effectiveness of antioxidants may be different during running because in addition to mitochondria and xanthine oxidase, the greater level of muscle damage associated with running is also likely to promote the release of RONS from ****ocytic cells and iron-catalyzed reactions in muscle.

Three groups have examined the influence of supplementation with vitamin C both before and after prolonged running on changes in IL-6, C-reactive protein, cortisol and malondialdehyde (Table 2). Data from these studies are equivocal. Thompson et al. [69] reported that supplementation with vitamin C (400 mg/day) for 2 weeks before exercise significantly attenuated serum IL-6 concentration 2 h after exercise, whereas it did not influence changes in the serum concentrations of C-reactive protein and cortisol or plasma malondialdehyde concentration. In contrast, vitamin C supplementation for 1 week before (1000 mg/day) [70] or 3 days after exercise (400 mg/day) [71] did not affect alterations in the plasma concentrations of IL-6, cortisol or malondialdehyde. These studies also reported no significant effect of vitamin C on muscle damage as indicated by changes in muscular strength, plasma creatine kinase activity and myoglobin concentration after exercise [69] and [71]. Another group examined the effect of supplementation with vitamin E (400 IU/day) for 3 days before prolonged running (Table 2). Although the plasma concentrations of IL-6 and cortisol increased significantly during exercise, there were no significant differences between the supplement and placebo groups [72].

[DRP7]

6.1. Discussion

As highlighted above, there are variable effects of antioxidant supplements on cytokine and cortisol responses to moderate- to high-intensity running lasting up to 2.5 h. Several factors may account for this variation, including the period of supplementation before exercise, the bioavailability of vitamins during exercise and endogenous antioxidant defenses related to the training status of participants.

The one study described above demonstrating that antioxidants attenuate the IL-6 and cortisol responses to exercise involved 2 weeks of supplementation with vitamin C [69]. In contrast, supplementation with either vitamin C or vitamin E for 1 week or less was not effective [70] and [72]. Clinical studies have reported that 2 weeks of supplementation with 200 mg vitamin C is the minimum period required to saturate plasma concentrations of ascorbic acid [73]. With respect to supplementation with vitamin E, in one study, plasma levels of α-tocopherol reached steady state after 4 to 5 days of supplementation with up to 1200 IU of dl-α-tocopherol [74]. Another study indicated that plasma α-tocopherol concentration plateaued after 2 weeks of supplementation with 800 IU dl-α-tocopherol-acetate [75]. The plasma concentrations of ascorbic acid alone and α-tocopherol and ascorbic acid may not be the most valid measure of tissue stores of these vitamins. However, the plasma concentrations of these vitamins correlate with tissue stores, as indicated by the correlation with leukocyte ascorbic acid content [76] and muscle α-tocopherol content [75]. Therefore, antioxidants may only alter inflammatory responses to exercise after a minimum period of 2 weeks. Future studies are warranted to investigate this issue.

The bioavailability of vitamins is likely affected by the dose, timing and dietary cofactors enhancing or inhibiting absorption. The bioavailability of vitamin C is significantly reduced at doses in excess of 200 mg vitamin C per day [73], and this may partially explain why supplementation with 1000 mg vitamin C did not alter the IL-6 and cortisol responses to exercise in the study by Nieman et al. [70]. Regular dietary intake of vitamin C most likely did not influence the results of the vitamin C studies above [69], [70] and [71] because in each study, dietary vitamin C intake during the supplementation period was similar between the supplement and placebo groups.

The bioavailability of vitamin E following supplementation depends on a variety of factors, including the dose, type of supplement (i.e., natural versus synthetic), half-life and dietary fat intake, all of which, in turn, influence pathways related to absorption and transport into the tissues [77] and [78]. Singh et al. [72] did not state the type of vitamin E that was given to the runners in their study. This factor could have influenced the effectiveness of the supplement because data from clinical trials indicate that the natural form of vitamin E, RRR-α-tocopherol, is more effective in reducing markers of inflammation than the synthetic form, all-rac-α-tocopherol [79]. Furthermore, the dose of 400 IU vitamin E used by Singh et al. [72] may have been insufficient. Clinical findings suggest that a threshold dose of ≥600?800 IU RRR-α-tocopherol appears to be most effective in reducing inflammation [79]. Lastly, the absorption of vitamin E is enhanced with higher intakes of dietary fat [74], [78] and [80]. It is therefore possible that the traditionally low-fat intake of endurance athletes may restrict the absorption of vitamin E, which means that less vitamin E is available to counteract the production of RONS during exercise.

As mentioned previously, it is possible that training adaptation in endogenous antioxidant defenses may explain some of the differences between these studies. Thompson et al. [69] used physically active but not endurance-trained participants, whereas the other studies used endurance-trained athletes [70] and [72]. Finally, the greater muscle damage imposed by running compared to cycling may increase the production of RONS by ****ocytic cells, thereby reducing the effectiveness of antioxidant supplements.

7. Antioxidant supplements and cytokine responses to downhill running

Two studies have investigated the influence of antioxidants on cytokine responses to downhill running. As explained in the introduction to the previous section, during running, more muscle damage means that there is probably a greater contribution of RONS from sources such as ****ocytic cells and iron-catalyzed reactions.

Thompson et al. [81] gave physically active males vitamin C (400 mg/day) for 2 weeks before and 3 days after 30 min downhill running at 60% VO2max. Plasma IL-6 concentration increased significantly during exercise in both groups, but there were no significant differences between the groups (Table 3). Vitamin C supplementation also did not influence muscle damage. Petersen et al. [82] provided recreational runners with a combination of vitamins C (500 mg) and E (400 mg) for 2 weeks before and 1 week after downhill running for 1.5 h at 75% VO2max. Although there was a greater IL-6 response in their study than that by Thompson et al. [81], the pattern of changes was similar between the supplement and placebo groups (Table 3). There were also no significant differences in plasma IL-1ra concentration and creatine kinase activity between the groups after exercise.

7.1. Discussion

These two studies involved 2 weeks of supplementation with vitamin C or a combination of vitamins C and E, which, as stated previously, appears to be the minimum period necessary to saturate plasma levels of ascorbic acid and α-tocopherol [73] and [75]. However, neither of these exercise studies reported any significant effects of antioxidant supplementation on cytokine responses and muscle damage after exercise [81] and [82]. Interestingly, the dose of vitamins C and E was similar in the studies by Petersen et al. [82] and Fischer et al. [61], but the period of supplementation was different between the two studies (2 weeks versus 4 weeks, respectively). It is possible that the longer period of supplementation can account for the greater attenuation of cytokines following exercise in the latter of these two studies. Petersen et al. [82] did not state what type of vitamin E was used in their supplement, while in their later study, the same group used RRR-α-tocopherol [61]. If different forms of vitamin E were used, as explained previously, this might account for the variable effects on cytokine responses after exercise. The natural form of vitamin E (RRR- or d-α-tocopherol) has twice the bioavailability of synthetic vitamin E (all-rac or dl-α-tocopherol) [83].

In explanation of their findings, Thompson et al. [81] suggested that vitamin C is less effective during exercise at lower intensity, which elicits smaller IL-6 responses. However, this concept seems unlikely because plasma IL-6 concentration increased to a greater extent after downhill running in the study by Petersen et al., yet supplementation with vitamins C and E did not alter the IL-6 or IL-1ra responses to exercise in that particular study [82]. Alternatively, as suggested previously, muscle damage may reduce the effectiveness of antioxidants. Further work is warranted to examine this concept.

8. Antioxidant supplements and cytokine responses to ultraendurance exercise

A number of studies have assessed the effects of antioxidants following ultramarathon and Ironman triathlon races. The cytokine response to ultraendurance exercise is considerably greater than any other form of exercise. This likely reflects not only the large metabolic demands of endurance exercise but also the substantial levels of oxidative stress and muscle damage resulting from such exercise.

8.1. Supplementation with vitamin C

Several studies have investigated the influence of vitamin C supplementation on alterations in IL-1β, TNF-α, IL-1ra, IL-6, IL-8, IL-10 and cortisol after ultramarathon running events [84], [85] and [86]. All three studies involved supplementation with 500 to 1500 mg vitamin C for 7 days before exercise (Table 4). The data from these studies are equivocal. One study reported that supplementation with 1500 mg vitamin C significantly attenuated the plasma concentrations of IL-1ra, IL-10 and cortisol after ultramarathon running. In contrast, supplementation did not significantly influence changes in the plasma concentrations of IL-1β, TNF-α, IL-6 or IL-8 concentration [84]. In another study, supplementation with 1000 mg vitamin C did not influence plasma IL-6 concentration after ultramarathon running, whereas it significantly enhanced serum C-reactive protein concentration 24 h after exercise [86]. This effect may have occurred as a result of the reduced circulating levels of cortisol in response to supplementation [86]. Lastly, in another study, athletes were given 1500 mg vitamin C for 7 days before and 1500 mg vitamin C during an ultramarathon race [85]. After the race, plasma cytokine concentrations were elevated, but there were no significant differences between the groups. Plasma cortisol concentration after exercise was also similar between the supplement and placebo groups. Furthermore, vitamin C may have promoted rather than reduced oxidative stress after exercise, as indicated by a trend (P=.051) toward higher plasma levels of F2-isoprostanes following exercise in the supplement group.

[DRP7]

8.2. Supplementation with vitamin E

The findings from other studies involving supplementation with vitamin E on its own or in combination with vitamin C are also equivocal. In one study, athletes were given 800 IU RRR-α-tocopherol for 2 months before an Ironman triathlon [87]. Vitamin E supplementation tended to enhance exercise-induced increases in the plasma concentrations of IL-6, IL-1ra and F2-isoprostanes as a marker of oxidative stress (Table 4). In contrast, vitamin E did not influence changes in plasma IL-8, IL-10 or cortisol concentrations. Another study provided athletes with a combination of 1000 mg vitamin C and 300 mg RRR-α-tocopherol for 6 weeks before an ultramarathon [88]. The plasma concentrations of TNF-α, IL-6 and C-reactive protein all increased significantly after the race, but there were no significant differences between the supplement and placebo groups. Antioxidant supplementation significantly reduced the plasma concentration of F2-isoprostanes after exercise.

8.3. Discussion

The findings reviewed above indicate that the effects of antioxidant supplements on inflammatory responses to ultraendurance exercise are highly variable. Some of these variations may be attributed to differences in the dose of supplementation, the timing of supplementation, the biological activity of vitamin C versus vitamin E and/or the exercise stimulus.

With respect to vitamin C, data from the three studies described previously suggest that over a short period of supplementation such as 7 days, only doses of vitamin C as high as 1500 mg/day alter the inflammatory response to exercise [84]. In contrast, doses of 500?1000 mg vitamin C per day over the same period seemed to be less effective [85] and [86]. However, it should be noted that in the study by Nieman et al. [84], the 1500-mg vitamin C supplement was consumed on the morning of exercise. Therefore, it is difficult to establish whether the attenuation of plasma cytokine concentrations after exercise reported in that study reflects (a) the influence of the supplementation period in the week before exercise or (b) the effects of a transient increase in circulating levels of ascorbic acid as a result of consuming the supplement on the morning of exercise. Evidence in favor of the latter of these two concepts is that the elimination half-life of vitamin C is 10 h [89] and that the bioavailability of vitamin C is significantly reduced at doses in excess of 200 mg vitamin C per day [73].

Vitamin E was also consumed on the morning of the Ironman triathlon in the study by Nieman et al. [87]. Furthermore, although the participants in this study were instructed to avoid race supplements high in vitamin E, vitamin E intake during the race was significantly higher in the supplement group compared with the placebo group [87]. α-Tocopherol is absorbed slowly into the bloodstream and has a long elimination half-life [78] and [89]. It is therefore possible that the vitamin E consumed before and during the race affected the results of this particular study.

In this vitamin E study [87], the greater cytokine response after exercise in the supplement versus the placebo group could be attributed to a possible pro-oxidant effect of α-tocopherol. Rietjens et al. [26] have proposed that under conditions of oxidative stress, increased levels of α-tocopherol can, in turn, generate elevated levels of α-tocopherol radicals and lipid peroxidation. When antioxidant systems are balanced, co-antioxidants inhibit the pro-oxidant action of α-tocopherol radicals, reducing them back to α-tocopherol. However, when α-tocopherol levels are elevated on their own during oxidative stress, the resultant levels of α-tocopherol radicals may overwhelm the capacity of co-antioxidants to reduce the α-tocopherol radicals [26]. If α-tocopherol radicals are formed during exercise in response to supplementation with large doses of vitamin E and oxidative stress, these radicals may act on NF-κB and/or calcineurin-NFAT pathways to enhance cytokine production. This concept would support the findings of Nieman et al. [87] that plasma cytokine (IL-6, IL-1ra) and oxidative stress (F2-isoprostanes) concentrations were higher after exercise in the supplement versus the placebo group. The vitamin E pro-oxidant theory may explain why supplements containing small amounts of vitamin E with co-antioxidants can provide greater benefits than vitamin E supplements alone [63]. Evidence in support of this concept is that in two of the studies described in this review [61] and [88], moderate amounts of RRR-α-tocopherol (300?400 mg) combined with ascorbic acid (500−100 mg) effectively reduced plasma F2-isoprostanes as a marker of oxidative stress after exercise. However, data from these two studies also indicated that reduced oxidative stress after exercise is not always associated with lower cytokine levels.

When comparing some of the studies above, changes in the anti-inflammatory cytokines IL-1ra and IL-10 and cortisol appeared to be greater after ultramarathon races with a distance of 90 km [84] than after 70-km races [85]. Interestingly, 1500 mg vitamin C attenuated the postexercise increase in anti-inflammatory cytokines and cortisol after the longer, but not the shorter, race. This trend suggests that the effects of vitamin C may depend on the duration of exercise and the resulting anti-inflammatory response. Plasma IL-6 concentration increased to a similar extent (not, vert, similar30?) after both races but was not influenced by vitamin C supplementation [84] and [85]. Therefore, vitamin C may influence some inflammatory variables but not others after ultraendurance exercise.

As suggested previously, the efficacy of antioxidant supplementation may also depend on the mode of exercise and the extent of muscle damage. Muscle damage may contribute to RONS production such that the capacity of antioxidant supplements to neutralize RONS is overwhelmed. Mastaloudis et al. [88] used a supplementation regimen (1000 mg vitamin C, 300 mg RRR-α-tocopherol for 6 weeks) similar to that of Fischer et al. [61] (500 mg vitamin C, 400 IU RRR-α-tocopherol for 4 weeks). However, Mastaloudis et al. found that the supplement did not significantly alter plasma levels of cytokines and C-reactive protein after exercise that involved muscle damage. In contrast, Fischer et al. reported attenuated plasma levels of cytokines, C-reactive protein and cortisol after exercise that did not cause appreciable muscle damage. It is possible that during ultraendurance exercise, the combined influence of metabolic demands, high levels of oxygen consumption and muscle damage exceeds the capacity of antioxidant supplements to attenuate cytokine production.

9. Antioxidant supplements and cytokine responses to local eccentric muscle contractions

Two studies have investigated the effects of antioxidant supplements on cytokine responses to local eccentric muscle contractions involving the elbow flexors or biceps muscle group. Unlike aerobic exercise such as that described in the previous sections, local eccentric muscle contractions do not involve a large increase in mitochondrial respiration but result in muscle damage. Cytokine production following this form of exercise is likely stimulated by RONS generated from ****ocytic cells and iron-catalyzed reactions in skeletal muscle.

In a study by Childs et al. [32], untrained individuals received a combination of vitamin C (12.5 mg/kg body weight) and NAC (10 mg/kg body weight) for 7 days after three sets of 10 eccentric contractions of the elbow flexors at 80% of one repetition maximum. Plasma IL-6 increased mildly after exercise but was not significantly different between the supplement and placebo groups (Table 3). There was evidence of greater oxidative stress in the supplement group after exercise, as indicated by higher plasma concentrations of lipid hydroperoxides and F2-isoprostanes. These data suggest that vitamin C and NAC might have pro-oxidant effects under conditions of exercise-induced tissue damage. This effect may have occurred via a reaction between ascorbic acid and Fe3+ released from skeletal muscle, which can result in the formation of RONS [32].

Using the same exercise protocol, this group conducted another study to examine the efficacy of a combination of antioxidants (300 mg mixed tocopherols, 300 mg flavonoids and 800 mg docosahexaenoate) for 7 days before and 7 days after exercise [90]. Plasma IL-6 concentration was relatively low after exercise (Table 3); however, the antioxidant supplement significantly attenuated plasma IL-6 concentration by around 80% 3 days after exercise compared with the placebo group. The median increase in plasma C-reactive protein concentration was also significantly smaller in the supplement group 3 days after exercise [90].

Therefore, although similar exercise protocols were used in each study, the effects of supplementation were different. In the first study, the antioxidant supplement appeared to promote oxidative stress, while it slightly reduced inflammation. In the second study, the antioxidant supplement reduced inflammation to a greater extent. These differences may be due to the different composition of the two supplements that were used. Alternatively, the differences may be due to the fact that in the first study, the antioxidant supplement was ingested after exercise, whereas in the second study, the antioxidant supplement was ingested both before and after exercise.

[DRP7]

10. Influence of regular dietary intake

When interpreting the data from some of the studies described in this review, the effect of regular dietary intake of antioxidants is also worth mentioning briefly. Some of the studies described recorded dietary intake of antioxidants during the supplementation period [69], [81], [86] and [87], and some studies instructed participants to avoid certain foodstuffs containing large amounts of antioxidant vitamins [69], [87] and [88]. The uptake of antioxidant vitamins from supplements is likely to be influenced by regular dietary intake. Beyond a certain level of dietary intake, concentrations of antioxidants within the circulation and tissues are saturated [73] and [91]. Consequently, athletes with low dietary antioxidants are more likely to benefit from supplements [92]. The consumption of other foodstuffs in the diet may also affect the bioavailability of antioxidant vitamins. For example, the intestinal absorption of vitamin E is dependent on the lipid content of recently eaten food as supplements taken with high-fat meals are better absorbed than those consumed with low-fat meals [74], [78] and [80]. Therefore, because not all studies monitored or attempted to regulate dietary intake of antioxidants during the supplementation period, these factors could have contributed to some of the variability between the studies.

11. Is antioxidant supplementation beneficial?

The equivocal nature of the research findings presented in this review precludes us from drawing any definitive conclusions regarding the effects of antioxidants on inflammatory responses to exercise. Further work is needed to improve our understanding of the relative contribution of the various stimuli and sources of RONS during different forms of exercise. Traditionally, sports science research has sought methods of reducing muscle damage and enhancing recovery, and this explains some of the interest in antioxidant supplements. However, data from recent studies indicate that the effects of antioxidant supplements on exercise-induced muscle damage are variable [69], [81], [93], [94], [95] and [96], which calls into question the role of RONS in the etiology of muscle damage. RONS may instead be a by-product of muscle damage. Importantly, RONS are now recognized as key mediators of cellular signaling and training adaptations [11]. Supplementation with large doses of antioxidants has been shown to attenuate some of the cellular signals that stimulate adaptation to exercise. For example, vitamin E reduces the beneficial effects of exercise training on cardiovascular risk factors such as progression of atherogenic lesions, plasma cholesterol concentration, aortic CAT activity and expression of endothelial nitric oxide synthase (eNOS) [6]. Furthermore, allopurinol blocks the exercise-induced oxidation of glutathione; the phosphorylation of p38, ERK1 and ERK2 MAPKs; the mRNA expression of Mn-SOD, inducible NOS and eNOS; and the activation of NF-κB in skeletal muscle [5]. Finally, large doses of antioxidants such as vitamins C and E may be ineffective [97], [98], [99], [100] and [101] or even harmful to health in some situations [102] and [103]. Therefore, further work is warranted to investigate if athletes should use antioxidant supplements during training to enhance recovery and performance.

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FINISHED NOW I WANT A CAKE!



The references will make a similar amount of text, so, I'll post them only upon special request.

[GeneGnomeX]

^^^ that third to last line there,


p38 MAPK mediates one pathway to PGC-1alpha & mitochondria biogenesis. So far I have it mapped out through NRF1 & 2 and beta adrenergic activation can increase PGC-1alpha, which when overexpressed downregulates GLUT4 (stims)

1: J Biol Chem. 2007 Jan 5;282(1):194-9. Epub 2006 Nov 12. Links
Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression.
Wright DC, Han DH, Garcia-Roves PM, Geiger PC, Jones TE, Holloszy JO.
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and in mitochondrial biogenesis in skeletal muscle. PGC-1alpha regulates and coordinates mitochondrial biogenesis, and overexpression of PGC-1alpha in muscle cells results in increases in mitochondrial content. In this context, it has been proposed that the increase in PGC-1alpha protein expression mediates the exercise-induced increase in mitochondrial biogenesis. However, we found that mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1alpha protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1alpha mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1alpha in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1alpha into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1alpha protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, delta-aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1alpha may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1alpha protein sustains and enhances the increase in mitochondrial biogenesis.

PMID: 17099248 [PubMed - indexed for MEDLINE]

I remember a thread by Dr. Dave about HSP, some evidence for vitamin E attenuating some of them and some have roles in membrane stability in protein folding IIRC

[ShadyShadow13]

well i didnt have time to read all .. and i feel like im back to school again . bio class
hmm i guess then it will be safe to say that limiting my vit C to not more than 2000 mg .. and talking it in a different time than my post workout .. something like in the morning and before sleep ..

thanx guys

[NO HYPE]

FINISHED NOW I WANT A CAKE!

Nice Dr.P.... Thank you for taking the time to post that.

[RB12]

so bear with me, I was just thinking this over; what effect would foods high in antiox properties post workout have? Theorizing that large amounts of antiox post workout should be avoided bc of their potential anti-inflamitory abilities and effects on protein synthesis, should items like blueberries and other fruits and veggies be avoided in pre and post workout meals? just curious on thoughts?

[NO HYPE]

Theorizing that large amounts of antiox post workout should be avoided bc of their potential anti-inflamitory abilities and effects on protein synthesis, should items like blueberries and other fruits and veggies be avoided in pre and post workout meals?

In my opinion.... there is no possible way to consume enough antioxidants through food, to actually elicit the same response as a concentrated and/or multiple concentrated extracts, so gobble those blueberries up.

[RB12]

In my opinion.... there is no possible way to consume enough antioxidants through food, to actually elicit the same response as a concentrated and/or multiple concentrated extracts, so gobble those blueberries up.

rofl, ok, thanks for the input

[EMISGOD]

For purposes of anecdotal contribution, I can definitely tell you that my gains have rather dramatically increased with the addition of my first anti-oxidant cocktail, which was Zinc, Vitamin C, Vitamin E and Co-Q10 taken before bed. They increased dramatically mainly because the frequency that I was getting sick decreased considerably. Nothing hinders gaining more than being down with an illness (well, injury excluded, of course).

That cocktail worked well for a while, but I would still get sick, sometimes very sick, at least once a year, which would throw off training and diet for up to a month, depending on severity. To my rescue came DS Vigor, which reduced the sick time from the aforementioned time frame down to a handful of days and decreased the symptoms considerably. I have charted the patterns of my sickness for literally years (including seasonal shifts) and while I have not found a cause, I can definitely tell what has impacted it the most positively.

[NO HYPE]

For purposes of anecdotal contribution, I can definitely tell you that my gains have rather dramatically increased with the addition of my first anti-oxidant cocktail, which was Zinc, Vitamin C, Vitamin E and Co-Q10 taken before bed. They increased dramatically mainly because the frequency that I was getting sick decreased considerably. Nothing hinders gaining more than being down with an illness (well, injury excluded, of course).

That cocktail worked well for a while, but I would still get sick, sometimes very sick, at least once a year, which would throw off training and diet for up to a month, depending on severity. To my rescue came DS Vigor, which reduced the sick time from the aforementioned time frame down to a handful of days and decreased the symptoms considerably. I have charted the patterns of my sickness for literally years (including seasonal shifts) and while I have not found a cause, I can definitely tell what has impacted it the most positively.

Great post.... repped.