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Study under review: Vitamin C and E supplementation alters protein signalling after a strength training session, but not muscle growth during 10 weeks of training
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Introduction

Antioxidants are often touted as miracle cure-all compounds, and two of the most commonly supplemented antioxidants, vitamins C and E, are included in a wide array of supplements and multivitamins. Vitamin C supplementation is especially common during the cold season, although evidence suggests this kind of supplementation is mostly beneficial for special populations, like people engaging in extreme physical exercise [1]. However, there is a growing body of evidence showing that vitamin C and E supplementation can negatively affect performance in competitive and recreational athletes alike.

Much of the previous research on antioxidant supplementation and performance involved some type of endurance exercise, where results have suggested that antioxidants may actually negate some of the healthy adaptations to training [2]. Training stresses muscles at a cellular level, involving pathways that utilize free radicals, and bigger and stronger muscles are partially a result of this stress. Because the exact effects of antioxidant supplementation on weight training are largely unknown, a recent trial sought to assess the effects of vitamin C and E supplementation on strength training adaptations in young, healthy individuals.

Who and what was studied?

The study under review was a double-blind randomized controlled trial assessing the effects of vitamin C and E supplementation on strength training and muscle metabolism.

The participants in this study were 32 young recreational strength trainees, who had been regularly performing strength training exercises, one to four times a week for the past six months. The mean age of the groups was in the mid-twenties. The vitamin group had five women, out of 17 total participants, and the placebo group consisted of six women, out of 15 total participants. Most of the trainees engaged in some sort of endurance training as well, but during the study, that was restricted to once per week at most. The participants were also instructed to stop taking any supplements in the two weeks leading up to the study to ensure that the only supplements they used were the studied vitamin C and E.

The study began with a one to four week phase devoted to training the participants in how to perform the strength tests (various single-joint isolation exercises such as biceps curls and leg extensions, which are standard for performance studies). This phase included three relatively light workouts per week (8-12 reps at the 15-rep max of the participants).

After that, the training protocol included six weeks of three sets at the participants' 9-11 rep maximum and then three weeks of three to four sets at their 6-8 rep maximum. Each week had four sessions with two upper body sessions and two lower body sessions, using a variety of compound and isolation exercises.

The participants were randomized to receive either placebo pills or a total of 1000 mg vitamin C and 235 mg vitamin E per day. This dosing was split into pre- and post-workout doses on training days, with half taken one to three hours before training and half within an hour after training. Non-training day supplements were split between morning and evening doses. The total daily doses of these antioxidants were substantially higher than the recommended daily intakes for vitamin C (90 mg for men and 75 mg for women) and vitamin E (15 mg for both men and women).

The participants were given advice on diet and post-workout protein intake, in order to help maintain a slightly positive energy balance. They also submitted a four-day weighed food diary at the start and end of the study, and recorded their supplement intake and training logs. This helped keep the study participants on protocol, and also served to signal the researchers to advise any participants who weren't eating enough protein (defined by the researchers as one gram per kilogram of body weight, minimum). Body weight and composition were studied with DEXA scans and muscle cross-section MRIs, which are widely used in training performance studies.

In addition to these long-term analyses, the researchers conducted acute muscle analyses on a subset of participants. These analyses included blood tests and muscle biopsies before and after a relatively strenuous session of leg presses and leg extensions. For these analyses, the participants ate a standardized breakfast, took either the vitamins or placebo, and then came to the lab to complete the testing. After the training, but before the post-training biopsies and blood work, the trainees took another dose of supplements or placebo.The researchers then performed a variety of molecular and biochemical analyses of the blood and muscle samples with the goal of understanding how vitamin C and E affect muscle metabolism and cell signaling pathways important for hypertrophy and muscle adaptation.

Participants in this RCT were young and mostly male. They were given high doses of vitamins C and E before and after training, as well as in the morning and evening of non-training days. Biopsied muscle was also tested to assess the direct effects of these vitamins on critical signaling pathways and muscle metabolism.

What were the findings?

Despite this long list of interventions, the participants were remarkably adherent to the study protocol. As one might expect from people eating more than maintenance calories and lifting weights four days per week, participants in both the placebo and the treatment groups got stronger. However, the placebo group showed greater strength gains than the vitamin group, although this was only statistically significant for biceps curls. This difference in strength did not translate to differences in hypertrophy, which could be due to a number of reasons, including variations in training response or history, the short timeframe or small sample size.

In the blood and biopsy sub-experiment, a number of signaling markers important for stress-response and protein synthesis-control were examined. The researchers identified a significant difference in activation (phosphorylation) of the MAPK proteins p38 and Erk1/2, with the placebo group showing significantly greater activation than the antioxidant group at 100 and 150 minutes after the training session.

Because MAPK proteins are activators of the molecular stress-response and play an integral role in muscle anabolic signaling [3], these results suggested that antioxidants may be reducing part of the 'go' signal for muscle growth/adaptation in response to training. Consistent with this, activation of p70S6K, an important control point for protein synthesis, was also reduced by antioxidant supplementation.

Conversely, ubiquitination, which is a general marker of protein degradation was lower in the treated group than in the placebo group, but ubiquitination alone is a poor marker of muscle tissue breakdown because it is associated with a wide variety of processes and is not specific to muscle. More specific markers such as the expression of muscle-specific E3 ubiquitin-ligases MurRF1 or Atrogin-1 (enzymes that tag muscle proteins with ubiquitin, marking them for destruction) would have been more informative here. As one might expect with no observable difference in hypertrophy, there was no difference in muscle protein synthesis rates between groups, which was further supported by a lack of change in various markers of protein synthesis, including AMPKα, PRAS40, or 4EBP1 phosphorylation.

Although both the vitamin and placebo groups gained strength, the placebo group appeared to have greater increases. Experiments on muscle tissue showed that the antioxidant vitamins appeared to interfere with critical signaling pathways involved in protein synthesis.

What does the study really tell us?

Overall, antioxidants blunted some, but not all of the measured signaling pathways that are important for the adaptive response to exercise. Although this was not sufficient to reduce the extent of hypertrophy between groups, it could explain the reduced upper-body strength adaptations in the antioxidant group. Although this only reached statistical significance for the biceps curl, the statistical power in this study was relatively limited by small sample-size. This suggests that the relatively minor suppressive effects of antioxidants on strength were likely real and warrant further investigation.

It is important to note that the antioxidants in this study were taken within an hour or two before/after training. A number of studies in recent years have demonstrated that reactive oxygen species (ROS) are important signaling molecules that drive molecular adaptation to exercise, and blocking the increase in oxidation [4] that occurs during exercise with antioxidants such as vitamin C and E may ultimately limit or negate some of the healthy, adaptive effects. Thus, this study supports what previous reports have suggested; taking antioxidant supplements around training time may limit gains. If you are going to take antioxidant supplements, be sure to separate them from your workouts as much as possible.

The big picture

A growing body of evidence indicates that high doses of vitamins C and E may have negative effects on a variety of athletic performance tests. While no significant changes were seen in hypertrophy levels, a significant difference in strength development was seen between placebo and vitamin treated groups, suggesting that further studies should evaluate longer term effects of chronic vitamin C and E supplementation on strength training and muscle hypertrophy.

This report is a follow-up to a previous report by the same group that studied endurance performance in people receiving vitamin C and E supplements. That initial report provided evidence validating their general experimental method and the effects of their supplementation regimen, but it was conducted with an emphasis on endurance exercise rather than strength training. This study was both a refinement of some of that study's methods as well as a change in focus to strength training.

The findings in this study and its endurance counterpart (as well as similar studies done by other groups in humans and animals) support the well-established idea that athletic adaptation is influenced by oxidation in muscle cells, and add to it that acute suppression of ROS by antioxidant vitamins may affect strength adaptation. As seen in Figure 1, it has been hypothesized that muscular force production, a proxy of hypertrophy and strength gains, is stymied by both too many antioxidants as well as excessive ROS. We don't yet know how much is too much in terms of antioxidants and ROS. But we do know that progressive adaptation to a moderate amount of ROS stress drives the cellular response to exercise, culminating in increased protein synthesis, reduced protein breakdown, and ultimately larger, stronger muscles. Therefore, it may be reasonable to think that bulk suppression of cellular oxidation levels with antioxidants may eliminate a signaling molecule that is important for adaptation to exercise. In a sense, we are shooting the messenger for muscle adaptations.

Figure 1: Biphasic effects of ROS on muscle force production

Frequently Asked Questions

Q. Does this mean I shouldn't take vitamin C and E?

While both of these antioxidants are essential, reports on the ultimate efficacy of supplementation in terms of aging, longevity, and disease are mixed and sometimes population-specific. Therefore, whether or not you should supplement vitamin C or E at all is a much larger issue than the effects of these vitamins on any one system or parameter. What the present study and other similar ones examining the effects of antioxidants on exercise does tell us is that if you choose to take vitamin C and/or E supplements, you should separate them from your workouts as much as possible.

Furthermore, as a general rule, it is best to get most of your antioxidants through eating lots of fruits and vegetables. Increased fruit and vegetable intake is associated with increased longevity and reduced incidence of many diseases, and these effects go beyond those of any single compound or supplement.

The decision is a bit easier for older adults, who seem to respond better [5] to vitamin C and E supplementation. This may be related to the higher oxidative stress levels associated with aging, but the mechanism is currently incompletely understood. This is further compounded by the fact that older adults may have a harder time combating colds and other minor illnesses, and vitamin E [6] supplementation can help reduce upper respiratory tract infections in the elderly while vitamin C [1] may help reduce the duration of the common cold. Overall though, antioxidant vitamins have increasingly performed poorly [7] in studies looking at cardiovascular outcomes and overall mortality, with some studies showing an increase in mortality from high doses. So don't take high doses of antioxidants willy-nilly, as marketing claims rarely if ever relay all the evidence on potential risks.

Q. What if I take recommended lower doses of vitamin C and E rather than the high doses in this study?

Because the effects seen in this study were very small and the doses were relatively high, it seems unlikely that the recommended daily intakes of these vitamins will affect strength training. If you are deficient in these vitamins, lower doses may very well help with general health and training progress, especially because vitamin C is involved in collagen production and maintaining immune function. Since this trial studied regular high intakes of supplements at training time, it does not mean that athletes who eat foods rich in vitamin C or E should stop eating these foods. Effects of isolated nutrient supplements often don't mirror that of nutrient-rich foods. However, athletes who choose to supplement with vitamins C and E (or other antioxidants) may want to time their supplementation as far away from training time as possible.

Q. What does this mean for other antioxidants?

A large number of studies in recent years have suggested that the ROS molecules are important chemical messengers that control a number of cell signaling processes, including those that drive the adaptive response to exercise. Evidence is mounting that antioxidant supplements taken in close proximity to workout times may negate some of these healthy adaptive effects of exercise by suppressing acute increases in ROS levels. The extent to which this happens and whether or not only certain antioxidants are problematic warrants further investigation.

What should I know?

Although the mechanism by which antioxidants affect performance is not completely understood, current evidence indicates that they do so by suppressing the activation of oxidation-driven signaling pathways important for muscle adaptation to exercise.There is some evidence that large doses of vitamins C and E taken in close temporal proximity to workouts may negatively affect adaptations to both strength and endurance training. However, vitamin C and E supplementation does not seem to have any effect on adaptations to strength training in older adults [5].

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See other articles with similar topics: Supplementation, Vitamin C, Vitamin E, Exercise, Muscle, Muscle Protein Synthesis, Resistance Training, Antioxidants, Exercise Recovery.

See other articles in Issue #02 (December 2014) of Study Deep Dives.

References