1- Featured Article: The Creatine Secret – Part 2: An Oxidant’s Nightmare
This Month’s Featured Article:
The Creatine Secret – Part 2: An Oxidant’s Nightmare
by Alfredo Franco PhD
Have you ever wondered why we must inspire oxygen to survive? In my cell physiology lecture, I would satirically explain that oxygen acts as the final electron acceptor during cellular respiration. Somehow, however, I don’t think that this response would satisfy many of you in my newsletter audience. Certainly, several of my students would also roll their eyes at this type of response. I would then need to take a step back and clarify that the cell provides itself with energy by shuttling electrons through a series of chemical reactions (housed within the mitochondria of the cell) known as the Electron Transport Chain (ETC). As electrons are passed from one member of the ETC to the next, small amounts of chemical energy are stored, which are then captured by the cell and invested in the formation of ATP, the cell’s energy currency. Unfortunately, as these electrons cannot be reused once they have exited the ETC, they must be immediately removed from the cell. It is at this point that oxygen plays it most important role: each oxygen atom we inspire has the ability to accept two of the electrons exiting the ETC. Furthermore, as the cell would rather not have rampant electrons free in the cytosol for the damage they could cause to cellular constituents, each electron liberated from the ETC is accompanied by protons (H+) to form hydrogen atoms (H). Two hydrogen atoms (two electrons and two protons) then combine with one oxygen atom to produce water, H2O. Therefore, the reason we inspire oxygen is to capture the electrons leaving the ETC; otherwise, the cell would die.
As our energy expenditure increases during exercise, however, more electrons are produced and greater amounts of oxygen are needed to capture these. Consequently, our rate of breathing increases with physical exertion. Ironically, the same feature that makes oxygen a good acceptor of electrons also makes it potentially harmful to the cell, its hunger for electrons. When the ETC is kicked into high gear, electrons are donated to oxygen without protons as their chaperones, thus creating “free radicals” of oxygen known as superoxide (.O2-). The dot denotes the presence of an unpaired electron that can reap havoc on an unsuspecting molecule. Superoxide is super-nasty since sets off a chain reaction of free radical production that may potentially kill the cell!
Free radicals produced from oxygen are also known as Reactive Oxygen Species (ROS). Superoxide is one of the most insidious of all ROS produced in biology. Superoxide breaks down the cell’s protective membrane as well as destroys its genetic material (DNA), leaving the cell vulnerable to environmental insult without recourse to bolster its defenses Superoxide also neutralizes one of our most important cellular messengers, namely Nitric Oxide, or NO. Taking NO out of play has very dangerous repercussions!
The body normally defends itself from free radicals with a battalion of antioxidants that it either produces itself or obtains through the diet. Molecules like oxygen (and superoxide) that steal the electrons from other molecules are known in chemistry as “oxidants”. Anti-oxidants, in turn, donate electrons to oxidants, thereby short-circuiting the death cascade. During normal activity, these antioxidants are able to neutralize free radicals as soon as they are produced. As oxygen consumption increases, however, the production of free radicals increases to the point where the body’s antioxidant defenses are overwhelmed, giving rise to a physiological scenario known as “oxidative stress”.
Glutathione is one of the most potent antioxidants that the body produces. Superoxide dismutase, catalase and glutathione peroxidase are examples of antioxidant enzyme complexes that the body manufactures. These antioxidant enzyme complexes work in organized succession to completely abolish the cascade of free radicals produced by superoxide. Nevertheless, despite the presence of powerful endogenous antioxidants, dietary antioxidants are still necessary to neutralize free radicals produced from heavy exercise. Importantly, if uncompensated for, oxidative stress during and following intense exercise will impede muscle recovering sufficiently to preclude subsequent muscle growth.
Environmental Sources of Oxidative Stress
Heavy exercise is not our only source of oxidative stress. Many of the noxious stimuli we encounter in daily life (pollution, radiation, herbicides, etc) exert their damage by producing free radicals. Cigarette smoke (ref 1) and alcohol consumption (ref 2) are two sources of free radicals that many of us purposefully self impose. That throbbing in your head you feel after a few too many pints is largely a consequence of free radicals. Indeed, I have generated my fair share of free radicals in my day.
Many experts are also now of the opinion that the decrements in mental and physical capacities often associated with aging are largely the result of accumulated free radical damage. Have you ever noticed how a heavy smoker appears old and wrinkled before their time?
Creatine Supplementation Helps Alleviate Oxidative Stress
Obviously, an athlete (as well as nearly everyone else) must take active measures combat oxidative stress. Recent evidence has now revealed that creatine possesses innate antioxidant properties that may confer part of its ergogenic benefit (ref 3). This advantage of creatine supplementation will further be fortified with the addition of folic acid and vitamin B6 to your supplementing regimen as explained next.
Direct Antioxidant Properties
Creatine (ref 3) and folic acid (ref 4) have recently been shown to be antioxidants in their own right. In fact, both these nutrients were shown to be effective at neutralizing superoxide. Therefore, supplementing with creatine and folic acid alone should improve your antioxidant defenses and promote muscle growth following intense exercise. However, the effects of B-vitamins go far beyond this one antioxidant mechanism.
It is now known that vitamin B6 channels homocysteine into the glutathione synthetic pathway (ref 5; also see figure below), making the best of a bad situation, so to speak. The potency of this pathway is dramatically demonstrated by the finding that rats fed a diet deficient in vitamin B6 exhibit severely attenuated antioxidant defenses including reductions in superoxide dismutase, glutathione and glutathione peroxidase (ref 6). Interestingly, both enzymatic and non-enzymatic (dietary antioxidants) superoxide scavenger activity were reduced in B6 deficient rats. Clearly, vitamin B6 is essential for mounting a robust antioxidant counter attack against the oxidative stress arising from intense exercise.
Homocysteine levels are reduced by three mechanisms: (1) creatine supplementation, by circumventing creatine synthesis; (2) folic acid and vitamin B12 supplementation, by methylating homocysteine to recreate methionine; and (3) vitamin B6 supplementation, by channeling homocysteine into the glutathione synthetic pathway. All three pathways improve our cellular methylation status while simultaneously fortifying our antioxidant defenses. In brief, the combination of these three sets of nutrients will take muscle anabolism to all new heights.
Indirect Antioxidant Properties
It is now widely accepted that several of homocysteine’s most dangerous traits stem from its behavior as an oxidant. For instance, homocysteine activates a cellular pathway that produces superoxide and ultimately gives rise to vascular disease (ref 6).
Last month I explained the benefits of combining creatine supplementation with the targeted intake of specific B-vitamins: (1) heightened methylation status, promoting muscle anabolism and cell survival; (2) reduced homocysteine levels, fending off many diseases; (3) accentuated creatine synthesis, reducing the need for creatine supplementation at high levels; and (4) increased mental acuity, improving our focus and emotional outlook.
This month I make the case that combining creatine and vitamin B supplementation further promotes muscle anabolism by enhancing an athlete’s antioxidant status. The body’s antioxidants arsenal, if sufficiently stocked, will allow muscles to fully recover following intense exercise. This, in turn, allows muscle anabolism to proceed unabated. If, on the other hand, our antioxidant defenses are not sufficiently fortified, muscle recover will be insufficient to allow subsequent muscle growth. It is thus important that an athlete fortify his/her antioxidant defenses in preparation for intense training sessions. The best way to improve your antioxidant status is to supplement your diet with essential antioxidant vitamins such as vitamin A, C, E, folic acid and vitamin B6. Add creatine to the mix and you now have a truly antioxidant formula with very anabolic repercussions!
Author’s Note: Creatine: A practical guide clearly explains how to combine creatine supplementation with safe nutrients for maximal muscle anabolism and improved overall health.
1. Mantle, D. and Preedy, V. R. (1999) Free radicals as mediators of alcohol toxicity. Adverse Drug Reaction Toxicology Review, Volume 18 (4), pages 235-252.
2. Lane, J. D. et al., (1996) Quitting smoking raises whole blood glutathione. Physiology and Behavior, Volume 60 (5), pages 1379-1381.
3. Lawler J. M. et al. (2002) Direct antioxidant properties of creatine. Biochemical and Biophysical Research Communications, Volume 290 (1), pages 47-52.
4. Stroes E. S. G. et al. (2000) Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circulation Research, Volume 86, pages 1129-1134.
5. Mahfouz M. M. and F. A. Kummerow (2004) Vitamin C or Vitamin B6 supplementation prevent the oxidative stress and decrease of prostacyclin generation in homocysteinemic rats. The International Journal of Biochemistry and Cell Biology, Volume 36 (10), pages 1919-1932.
6. Taysi. S. (2005) Oxidant/antioxidant status in liver tissue of v itamin B6 deficient rats. Clinical Nutrition, Volume 24, pages 385– 389.
7. Ungvari Z. et al. (2003) Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase. Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 23 (3), pages 418-424.
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