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The emerging case against antioxidant supplements
Len Kravitz, Ph.D.

Skeletal muscles are intricately designed molecular machines for producing work and force. During exercise, particularly more intense endurance training, free radicals are produced from mitochondrial and non-mitochondrial sources. These free radicals have both beneficial and harmful actions in biological tissues. To thwart the negative effects of free radicals, exercise enthusiasts have followed the advice of some experts with the supplementation of large does of antioxidants, including vitamin C, vitamin E and carotenoids. Newer research suggests this supplementation may actually blunt favorable adaptation in muscle (Merry and Ristow, 2015) and is the focus of this column.

What is Oxidation and Reduction?
Atoms are composed of a nucleus, neutrons, protons and electrons. Protons are the positively charged particles near the nucleus and electrons are the negatively charged particles that surround or 'orbit' around the atom. Chemical reactions tend to involve the movement of electrons, leading to the formation or breaking of chemical bonds. Oxidation is a term that means the loss of one or more electrons. These molecules losing the electrons are said to be oxidized. Some atoms and molecules in the body lose electrons more easily than others. Oxidation occurs in conjunction with a chemical process called reduction. Reduction is the process a molecule gains one or more electrons. Therefore, in an oxidation-reduction reaction (referred to as a redox reaction), one atom or molecule will transfer an electron(s) to another molecule.

What is a Free Radical or Reactive Oxygen Species?
Usually, reactions in the body do not leave a molecule with an odd, unpaired electron. But when this occurs, free radicals are formed. Free radicals are very unstable and assault (or react) with other compounds, trying to capture that needed electron to gain stability (i.e., become less reactive). When the 'besieged' molecule loses its electron, it becomes a free radical itself, beginning a chain reaction. Once the process is started, it can cascade leading to damage to cell membranes, enzymes and DNA (Steinbacher and Eckl, 2015). Oxygen-derived free radicals, called reactive oxygen species (or ROS, because they contain oxygen molecules), are formed in the mitochondria (energy power house of the cell) and various enzyme reactions as part of normal aerobic life. It is important to note that not all ROS are 'bad.' Some ROS help to fight off viruses, bacteria and unwanted microbes in the cell. However if too many ROS are formed, they may contribute to serious health conditions such as heart disease and cancer. Alas, free radicals can come from the sun (or any type of radiation), environment (including cigarette smoke and pollution), household chemicals (pesticides), unhealthy fats and stress.

What are Antioxidants and Oxidative Stress?
Antioxidants benefit the body by neutralizing or disarming the ROS, interrupting the ROS chain of reactions. Antioxidants donate an electron to ROS to stabilize them, without becoming free radicals themselves. The body cells manufacture many of these antioxidants to ward off invading organisms. Antioxidants also occur naturally in plant-based foods. Some of the well-known antioxidant compounds are flavanols (found in chocolate), resveratrol (found in wine), catechins (found in tea) and lycopene (found in tomatoes). Other popular antioxidants include vitamins A (beta-carotene), C and E.

Oxidative stress refers to an unbalanced cellular state in which the ROS outnumber the antioxidant defenses. Oxidative stress is associated with the pathogenesis of numerous diseases, including cancer, cardiovascular disease, diabetes and neurodegenerative diseases (Merry and Ristow, 2015).

The Antioxidant Role of Exercise
Merry and Ristow (2015) explain that exercise increases, or upregulates, the production of many antioxidants. The authors continue that the natural antioxidant effect of exercise is potentially a mechanism underlying the health-promoting benefits of regular exercise. From their research review, the scientists argue that over-supplementation with antioxidant supplementation may be potentially harmful to the ROS functioning as well as the ROS signally mechanisms. Merry and Ristow continue that exercise helps to regulate antioxidant responses in a more specific manner, counteracting the unwanted effects of non-discriminately scavenging ROS.

Antioxidant Supplementation for Exercise: To Supplement or Not Supplement?
Merry and Bristow (2015) highlight that the cellular investigation of the effects of antioxidant supplementation on exercise training-induced alterations is at an preliminary level.
Recently, Cumming et al., (2014) investigated the effects of vitamin C and E supplementation and endurance training on adaptations in endogenous antioxidants and heat shock proteins (HSP). Thirty seven males and females were randomly assigned to receive Vitamin C and E (C + E; C: 1000 mg, E: 235 mg daily) or placebo group, and underwent endurance training for 11 weeks. The study results indicate that vitamin C and E supplementation did not positively or negatively affect the activation of several metabolic pathways measured. However, the vitamin C and E group showed indications of inhibited tolerability toward exercise-induced stress that in the long run, or during periods of very intense exercise, may delay recovery and not allow for optimal gains in physical performance.

In another recent investigation (Paulsen et al., 2014), 54 young women and men were randomly allocated to receive either 1000 mg of vitamin C and 235 mg of vitamin E or a placebo daily for 11 weeks. During supplementation, the participants did endurance training consisting of three to four running sessions per, divided into high-intensity interval sessions >90% of maximal heart rate (HRmax) and steady state continuous sessions. Maximal oxygen uptake, submaximal running and a 20 meter shuttle run test were assessed as well as several biomarker adaptations to cardiovascular exercise. Results shows that the daily vitamin C and E supplementation minimized specific markers of mitochondrial biogenesis following endurance training. The authors concluded, "Consequently, vitamin C and E supplementation hampered cellular adaptations in the exercised muscles, and although this did not translate to the performance tests applied in this study, we advocate caution when considering antioxidant supplementation combined with endurance exercise."

A recent review article by Steinbacher and Eckl (2015) made the following summary observations. It is well-understood that muscle contractions during exercise lead to elevated levels of reactive oxygen species (ROS) in skeletal muscle. ROS as noted above, potentially have several negative effects. However, Steinbacher and Eckl continue that some of these exercise-produced ROS produced are involved in very positive signaling messages that enhance muscle development. They also note the regular endurance training enhances the development of the cell's specific antioxidants that ward some of the deleterious ROS effects. The authors summarize, "a diet supplemented with exogenous antioxidants such as vitamins appears to prevent health-promoting effects of physical exercise in humans."
In the Merry and Ristow review article (2015), the authors conclude, there is a growing body of literature signifying antioxidant supplementation may hinder or prevent the activation of important adaptations, such as muscle mitochondrial biogenesis, insulin sensitivity and hypertrophy

Final Observations
The new research clearly shows that some ROS, particularly some produced during endurance exercise, are beneficial to cellular processes (See Figure 1). As well, with exercise training, it is well defined that exercise develops and enhances a very specific team of antioxidants that ward of the effects of harmful ROS. Presently, there is no meaningful evidence for exercise enthusiasts to engage in antioxidant supplementation for exercise performance. Also, since antioxidants are naturally found in plant-based molecules, the research suggests that a diet should include recommended levels of vegetables, fruits and whole grain foods, to help combat or balance out the cellular ROS production.

Figure 1. The Beneficial Effect of Exercise, Diet, and Antioxidants and Some ROS

Cumming, K.T., Raastad, T., Holden, G. (2014). Effects of vitamin C and E supplementation on endogenous antioxidant systems and heat shock proteins in response to
endurance training. Physiological Reports, 2(2), 1-14.

Merry, T.L. and Ristow, M. (2015). Do antioxidant supplements interfere with skeletal muscle
adaptation to exercise training? Journal of Physiology, pp. 1-13, DOI: 10.1113/JP270654
Paulsen, G., Cumming, K.T., Holden, G. (2014). Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial, The Journal of Physiology, 592(Pt 8), 1887-1901.

Steinbacher, P. and Eckl, P. (2015). Impact of Oxidative Stress on Exercising Skeletal Muscle, Biomolecules 2015, 5, 356-377; doi:10.3390/biom5020356