Are You Getting Rusty? How Free Radicals Damage Muscles and How To Overcome Them

by John Berardi

from http://www.johnberardi.com/articles/supplementation/rusty.htm
First published at www.t-mag.com, Jun 6 2002.

Rusty Hubcaps and Rusty Kneecaps

Ever notice rust on your hands after working out? Sure you have. Plenty of guys favor those old, slightly rusty 45-pound plates at their local gym. But have you ever thought about why they've rusted? Or if you might be doing the same?

Living in an oxygen-rich environment (the air is about 21% oxygen) allows you to exercise intensely, metabolize food, and do so many other things. Heck, this very oxygen-rich environment has helped life evolve on this planet. But while oxygen is certainly beneficial on many levels, its presence and function comes at a price.

Just as the metal plates at your gym and the floorboards of your '72 Pinto slowly oxidize (rust), so do the cells/tissues of your body. And it's this oxidation of your bits and pieces that some scientists think causes many of the diseases of aging. So let's go on a little trek into your cells and see why antioxidant nutrition might be a necessity…

Next On Dateline: "When Oxygen Goes Bad"

Whether you like it or not, we're primarily aerobic (oxygen consuming) organisms. To put this into perspective, under normal resting conditions, we consume around 3.5ml of oxygen per kilogram of body mass per minute. This means that if the average 80kg individual were to lie in bed all day, he/she would consume about 403L of oxygen in that day. Obviously if this individual gets up to exercise, to move around, or even simply to roll over and change the dressings on their bedsores, the oxygen requirement would go way up. Good thing the government isn't taxing oxygen!

So why such a huge amount of oxygen consumption? Well, this huge oxygen consumption is primarily used to drive cellular respiration, to metabolize nutrients, and to produce ATP for energy. All of this occurs at the mitochondrial level and within this organelle (specifically the cytochrome level of the electron transport chain), enzymes are present to assist in the processing of this oxygen. While these enzymes have evolved to efficiently process oxygen during the generation of energy, about 2-5% of all the oxygen flowing through this energy manufacturing warehouse "goes bad," forming reactive oxygen species (ROS) and free radicals.

For the purposes of this article we'll consider ROS and free radicals one in the same and refer to them as pro-oxidants for the sake of simplicity. After all, each of these little cellular scavengers can become the equivalent of micro sized wrecking crews banging up your cellular parts. In more scientific terms, the chemical structure of these pro-oxidants is such that they contain extremely volatile unpaired electrons. These unpaired electrons readily react with cellular components such as proteins (structural, contractile, enzymatic), membrane lipids, and even the nucleotides within DNA and RNA, changing the structure of these molecules. This places every part of the cell at risk for radical-induced damage and alteration!

Bring Out the Heavy Artillery

Fortunately for us, with all of this oxygen processing, we are in possession of both well-developed internal (endogenous) enzymatic anti-oxidant defenses as well as the ability to consume foods that can protect against these cellular scavengers. These defense mechanisms step up as soon as the cell is challenged by excessive pro-oxidant activity and attempt to maintain a favorable pro-oxidant to anti-oxidant balance.

Exercise training provides a good example of this principle in action. It's been well documented that moderate intensity exercise increases pro-oxidant production. However, we all know that exercise is good for you and in fact, protects against many of the diseases associated with radical induced damage. So, what gives? Well, the body responds to moderate intensity exercise training with an upregulation of the natural anti-oxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPX). Therefore, although exercise causes an increase in radical formation, the physiological response to this actually improves the pro-oxidant to anti-oxidant ratio.

Fish oil supplementation provides another good example of this phenomenon. Since fish oil is extremely susceptible to oxidation both in the body and outside of the body (that's why it's kept in opaque containers), some researchers have reported an increase in pro-oxidant formation with fish oil supplementation. However, don't abandon your fish oil supplements just yet. Since the research demonstrating that fish oil supplementation provides protection against many of the diseases of aging is clear-crystal clear-you should be asking yourself whether something else is going on here. Well, there is. Research has demonstrated that fish oil supplementation actually increases the genetic expression of several genes that protect against free radicals (Takahashi et al 2001), again creating a more favorable pro-oxidant to anti-oxidant ratio.

Exercise Mode and Oxidation

As you might have guessed, different modes of exercise lead to different radical-generating mechanisms. Therefore both intense strength exercise as well as intense aerobic exercise have been shown to increase the production of pro-oxidants through three distinct mechanisms-increased metabolic (mitochondrial) oxygen processing, ischemic-reperfusion injury, and muscle micro-trauma/repair (otherwise known as leukocyte radical production). These mechanisms are described below.

Endurance Athletes and Increased Mitochondrial Oxygen Processing
As mentioned earlier, the enzymes of the mitochondria can produce pro-oxidants during energy metabolism, even at rest. Therefore it stands to reason that during intense aerobic activity, where oxygen processing occurs at rates 10-20 fold above resting oxygen consumption, more radicals will be generated. In fact, this increase in oxygen consumption leads to a 2-3-fold increase in free radical levels. While the natural anti-oxidant enzymes can normally neutralize free radical damage at rest, during exercise the increase in oxygen radicals may be more than these antioxidants can contend with.

Weight Training and Ischemic-Reperfusion Injury

Ischemia is defined as inadequate blood flow and/or inadequate oxygen delivery to the tissues of the body. While usually used in reference to the hypoxia (low oxygen) seen during myocardial infarction (heart attack), ischemia can also be seen in both skeletal muscles and various organs during weight training.

The typical static or moderate duration contractions associated with strength training can effectively "pinch off" the skeletal muscle, not allowing blood to circulate through this tissue. As described above, this could lead to hypoxia and ischemia within the skeletal muscle.

As well all know, once the contraction is over, however, blood rapidly refills the muscle, creating a huge pump. What you might not have known is that this rapid refilling can lead to something known as reperfusion injury. Reperfusion injury occurs, obviously, as blood rapidly re-oxygenates a tissue. Therefore, after a muscle contraction, blood rapidly flows back into the muscle and rapidly re-oxygenates it. Not prepared for this rapid influx, the mitochondria, myoglobin, and hemoglobin may form excessive amounts of pro-oxidants, thus injuring the skeletal muscle with radical induced damage.

While the skeletal muscle is certainly at risk for ischemic-reperfusion injury, other tissues may be at an even greater risk. It should come as no surprise that during exercise, blood is shunted away from internal organs and re-routed to the skeletal muscles. In fact, at rest, 15-20% of cardiac output (or 0.75-1L of blood per min) is shunted to the muscles. However, during maximal exercise, 80-85% of cardiac output (or 20-21.25L of blood per minute) is shunted to the muscles. Obviously with all this blood going to the muscle during exercise, there's less blood going to the organs. After the exercise session, there is a large influx of blood back into the organs and this influx may lead to the same type of reperfusion injury described above.

Weight Training and Muscle Micro Trauma/Repair

This final mechanism is interesting in that it doesn't actually occur during exercise; it's a post exercise phenomenon. As we know, intense strength exercise can lead to both mechanical and oxidative damage in skeletal muscle. This damage includes the loss of structural and contractile integrity as well as damage to the lipid membranes of the muscles. After exercise-induced microtrauma (damage), there's a period of inflammation and soreness characterized by neutrophil and monocyte (macrophage) infiltration.

In addition, leukocytes (white blood cells) are activated to initiate repair. Data on this phenomenon are displayed in Muscle Masochism, Parts I and II. While these immune cells are excellent in their role of removing damaged muscle fibers, these same immune cells lead to free radical generation. This is necessary as the free radicals can help clear away microscopic tissue fragments/debris. What this means is that both the weight training session and the recovery from this session can cause free radical-induced damage.

As an interesting side note, it's currently unclear as to which came first, the radicals or the damage. It seems as if there's a downward spiral effect. Acute exercise leads to free radical production. These radicals (as well as other mechanical factors) can cause damage to cytoskeletons, membranes, and other cellular components of skeletal muscle. Once this damage occurs, leukocyte radical production is initiated to clear away damaged fibers, leading to the release of more free radicals and more radical-induced damage. And so on until the next training bout.

So How Bad Is It?

Reviewing the three mechanisms listed above, it's scary to think about what's happening to our muscles during and after aerobic or strength training. But remember, our bodies do have some complex mechanisms designed to deal with alarming physiological events. But the question remains-are these mechanisms good enough?

Most of the research looking at the exercise and oxidation has been done in endurance athletes. In these individuals exercise training leads to increased endogenous ("produced within") antioxidant enzyme concentrations as well as increased activity of these antioxidants. Therefore just as VO2 max, capillarization, mitochondrial density, and cardiac output increase in order to facilitate future exercise bouts, so do the antioxidant defense systems. One question remains though. With very intense exercise, do these defense systems increase enough to balance out the increased levels of pro-oxidants? Many researchers believe that the answer may be no.

Scott Powers, PhD and well-known antioxidant researcher has been quoted as saying, "It is well known that intense or prolonged exercise results in oxidative injury to skeletal muscles…Further there is growing evidence that radicals contribute to muscular fatigue…Therefore it's not surprising that there is strong interest in the effects of antioxidant supplements on exercise performance."

Animal data has shown repeatedly that muscle fatigue can be delayed in controlled in vitro muscle preparations perfused with antioxidants. Human studies have also indicated that increasing the concentration of endogenous antioxidants (i.e. increasing glutathione concentrations via whey protein supplementation) as well as providing antioxidant supplementation can improve performance. As is often the case, however, human studies on this topic are rather equivocal ("back-and-forth") regarding performance enhancement. Still, antioxidant benefits appear to be more than theory.

Since we specifically discussed endurance athletes, let's address weight-training athletes. Unfortunately, very few data have been collected in these individuals. However, since enzymatic adaptations occur primarily in slow-twitch muscle fibers (which are more mitochondrially dense and therefore contain more antioxidant enzymes than fast twitch fibers), athletes with a high percentage of fast twitch fibers may be at greater risk of radical-induced damage.

Since there's a clear increase in pro-oxidants with intense strength and endurance exercise as well as a decrease in plasma concentrations of vitamin E, vitamin C, coenzyme Q10 (all antioxidant vitamins/nutrients), perhaps athletes training at a high intensity may need more than what the body can naturally provide. After all, even those athletes consuming what's traditionally defined as a "nutritious, well balanced diet" see these reductions in plasma concentrations of some of the antioxidants. In this scenario, supplementing with antioxidant nutrients may be necessary.

Rarely is Any Physiological Phenomenon All Bad

Before we discuss which nutrients may assist in preventing pro-oxidant induced damage in hard training athletes, we want to caution you against developing a hatred for pro-oxidants.

Sure, the appearance of too many pro-oxidants in the body is obviously a bad thing as these radicals can damage important cellular components. But just like with cortisol, estrogen, and dozens of other necessary physiological compounds, pro-oxidants in small quantities are necessary and can even be beneficial.

Small quantities of radicals may be beneficial to cellular communication and cellular defense. It's well known that several intracellular messengers (cAMP, diacylgycerols, etc) signal the onset of many cellular processes. There's now evidence that radicals may perform similar roles. Lipid peroxidation is one mechanism by which this can occur.

In case you didn't know, lipid peroxidation is the process by which free radicals oxidize the membranes of different body cells. While typically seen as a negative thing, this process of breaking down the cellular membrane is one way that the membrane renews itself. In addition, this lipid peroxidation can release some mediators of immune function and inflammation known as eicosanoids.

Free radicals can also interfere with enzymes that promote the formation and secretion of corticosteroids as well as the formation of inflammatory prostaglandins.

Additionally, free radicals are involved in the destruction of bacteria and viruses as well. They both help assist in the removal of these invaders as well as stimulating the gathering of immune cells.

Finally, even the leukocyte "oxidative burst" is necessary to destroy old or damaged tissue in order to promote new tissue growth and muscle hypertrophy.

So, don't hate free radicals altogether. In necessary quantities, they may be quite friendly. It's only when the pro-oxidant: anti-oxidant ratio gets out of whack (as in hard training athletes) that you need to worry about excessive cellular damage, poor performance, and hampered recovery. This suggests that excessive antioxidant support may actually be harmful in itself. Not only might it interfere with some necessary and beneficial physiological processes, but also with the potential toxicity of several antioxidant herbs, vitamins, and minerals, you may cause a host of other problems.

Antioxidant Nutrition

So now that you understand why you might consider taking antioxidant supplements as well as understand that there is such a thing as too much, let's discuss some of the available antioxidants. (Those that are marked with an asterisk deem special attention.)

Vitamins and Minerals

Vitamin A - This lipid soluble vitamin has been shown to possess antioxidant properties, offering protection against lipid peroxidation, oxidative damage to proteins, and LDL oxidation. While these benefits are certainly desirable, very little research has been done in athletes since vitamin A toxicity is likely at higher doses. Interestingly, while plasma vitamin A decreases with exercise training, skeletal muscle vitamin A increases. In our opinion, as long as you're getting your RDA (900ug per day), no supplemental vitamin A is necessary or encouraged.

Beta Carotene - The carotenoids are a group of lipid soluble molecules (including lycopene, alpha and gamma carotene, canthaxanthin, lutein, etc), some of which are converted to vitamin A. However, some of the carotenoids have vitamin A independent roles including radical quenching, immune enhancement, and the induction of detoxification enzymes. Beta-carotene and lycopene are the best studied for these properties as well as their role in deterring cancer and heart disease. While there are very few exercise data, exercise does reduce plasma carotenoids. Supplementation with a combination of vitamins C, E, and beta-carotene can reduce lipid peroxidation at rest and at different exercise intensities as well as protecting against glutathione levels and muscle damage. We recommend supplementing with perhaps 5,000-10,000 international units daily.

Vitamin C - Ascorbic acid, is a very well researched water-soluble vitamin that has strong antioxidant properties. Vitamin C has the interesting ability to act as a primary non-specific antioxidant (it removes all radicals) as well as the ability to regenerate vitamin E. This can lead to a reduction in free radical production during exercise as well as a reduction in muscle soreness and damage. While vitamin C has a host of benefits, its antioxidant properties have to be weighed against its pro-oxidant properties. You see, vitamin C has the ability to increase dietary iron absorption. Iron is a potent pro-oxidant and linked to cardiovascular disease, particularly in men. And in excess, vitamin C itself can actually be a pro-oxidant. So moderate your doses. We recommend 250mg of vitamin C 1-2x daily (in addition to what your diet provides and not in conjunction with iron-rich meals).

Vitamin E - This lipid soluble vitamin is the most heavily researched antioxidant vitamin as members of the vitamin E family play roles in immunity, aging, exercise, heart disease, and cancer. For exercisers, muscle trauma can be attenuated with vitamin E supplementation, having favorable effects on lipid peroxidation, release of tissue enzymes, and protein damage/catabolism. While very large doses of vitamin E can be toxic, there is a wide therapeutic range. However, to maximize the benefits while minimizing the risks, 400IU should be taken 1-2x per day (in addition to what your diet provides).

Selenium - Selenium, a trace mineral essential to natural glutathione peroxidase structure and function, can increase endogenous GPX levels (much like the cysteine donor, whey protein). However, whey protein supplementation has shown to also improve performance while selenium has not. With its narrow range of toxicity, and apparent lack of efficacy, whey protein may be better and safer than additional selenium supplementation above what the diet can provide.

Zinc - Zinc, a trace mineral, is a structural component of the antioxidant enzyme, superoxide dismutase (SOD; the cytosolic form), but it's thought to have independent antioxidant properties, including membrane and protein stabilization. Since zinc balance is often unfavorable in athletes and zinc plays a variety of roles in physiological function (beyond antioxidant benefits), we suggest consuming at least 11 mg daily but not more than the tolerable upper limit of 40 mg per day.

Maganese - Maganese, a trace mineral, is a structural component of many enzymes and acts much like zinc in that it is a component of antioxidant enzymes (mitochondrial SOD) as well as an independent antioxidant. Maganese has been shown to decrease oxidative brain injury, LDL oxidation, and atherosclerosis. However, it is our opinion that 2-5mg per day, coming from food sources, is a sufficient intake and additional supplementation is unnecessary.

Copper and Iron - These trace minerals have many cellular functions including antioxidant potential. However, both of these are easily oxidized and can, in fact become pro-oxidants. Therefore the recommended intake of 0.9-3.0 mg of copper and just 8-10 mg of iron (for men) should not be exceeded. This iron limit may be difficult to maintain for serious carnivores but just try not to supplement any additional iron.

Miscellaneous

Polyunsaturated Fatty Acids (Corn Oil, Soybean Oil, Flax Oil, CLA, Fish Oil) - At this point we should discuss the pro-oxidant potential of polyunsaturated fatty acids (omega 3s and 6s). Polyunsaturated fats become incorporated into cell membranes and due to their relative instability, can be easily oxidized. But, as mentioned earlier, omegas 3s (and to some extent CLA) increase endogenous levels of antioxidants and shift the body toward a better pro-oxidant: anti-oxidant ratio. In fact, some anti-cancer benefits of special polyunsaturates may even be reduced by other antioxidants. Therefore with all of the health benefits of omega 3s, their pro-oxidant status is not a big concern. We suggest that >33% of total fat intake should come from polyunsaturated fatty acids; with about half of this intake in the form of omega 3s.

Monounsaturated Fatty Acids (Olive Oil, Canola Oil) - Monounsaturated fatty acids are more resistant to peroxidation than their polyunsaturated counterparts. In fact, data show that consumption of these fatty acids can actually reduce markers of tissue oxidation. Since monounsaturated fatty acids lower cholesterol levels, LDL cholesterol, and LDL oxidation, they should be a substantial part of any sound nutritional regime. We suggest that >33% of total fat intake come from monounsaturated fatty acids as found in olive oil and peanuts.

Whey Protein - See selenium. Antioxidant benefits come from as little as 20g of high quality, whey protein isolates per day.

Co-Enzyme Q10 (Ubiquinone) - Ubiquinone is a naturally occurring part of the electron transport chain and antioxidant. It may act as a direct antioxidant as well as an indirect one, regenerating vitamin E. Exercising individuals have reduced levels of ubiquinone in the muscle. While CoQ10 supplementation can normalize muscle levels, the data are widely mixed with some studies showing a benefit, some showing no benefit, and others showing negative effects. Therefore we do not support the use of CoQ10 supplementation at this time.

Alpha Lipoic Acid - ALA is an interesting molecule as it is both lipid and water-soluble and is present in mitochondrial proteins necessary for oxidative metabolism; is a cofactor for dehydrogenase enzymes; enhances glucose disposal; and can scavenge numerous ROS. Research has also shown that ALA improves mitochondrial function and therefore age associated metabolic decline. While ALA's role in glucose disposal as well as its antioxidant properties need to be clarified, we believe that perhaps 300 of ALA per day can be beneficial in terms of health and body composition.

Polyphenols - Although there are very little data examining the antioxidant effects of the following compounds in exercise, we decided to include them here due to their popularity as well as the benefits seen with respect to other physiological parameters. More research is certainly needed to confirm these benefits as well as to help make recommendations as to their intake. Food, herb, and drug interactions may be a concern with these compounds however, for what it's worth, these compounds do have a long history of use in other cultures.

Milk Thistle - This herb, otherwise known as silybum marianum, contains a host of active compounds and is most well known for their hepato-protective effects (liver protection). These effects may be due to the antioxidant benefits of milk thistle in the prevention of lipid peroxidation and the protection against glutathione depletion. This herb also possesses numerous other detoxifying effects.

Pine Bark (Pycnogenol) - Pycnogenol is the main active compound in the French maritime pine, pinus maritime. Pycnogenol has strong free radical scavenging activity. Its benefits include the regeneration of vitamin C, protection of endogenous vitamin E and glutathione from oxidative stress, and up regulating oxidant-scavenging systems.

Grape Seed Extract - The polyphenols found in grape seeds are effective in scavenging free radicals and preventing against lipid peroxidation as well as DNA fragmentation. In addition, grape seed extract may be able to protect against ischemic-reperfusion injury. This extract may in fact be better than vitamin C and E at similar doses. Time (and more data) will tell.

Green Tea - Green tea, in our opinion, should be a staple beverage of any dietary regimen. In addition to the thermogenic, anti-cancer and cardio-protective benefits, green tea prevents lipid peroxidation as well as aiding in the cellular defense of the ROS released during carcinogenesis.

Ginkgo Biloba - The leaves and fruit of the ginkgo plant have been used for over 5,000 years in China. While beneficial in the treatment of peripheral artery disease and cerebral insufficiency, ginkgo may also be beneficial in scavenging free radicals generated during ischemic-reperfusion injury and inflammation.

Move Over Rust-Oleum

Since the goal of this article is to give you the necessary information to rustproof your cells, here's a quick recap of our recommendations:

1. Total dietary fat intake should be made up of at least 1/3-monounsaturated fatty acids (olive oil) and 1/3 polyunsaturated fatty acids (much of these coming from omega 3 fatty acids like fish oil and flaxseed oil).

2. Consume at least 20g of protein per day from high quality whey protein isolates.

3. Supplement dietary intake with the following:

• Vitamin C - 250mg 1-2x per day
• Vitamin E - 400 IU 2x per day
• Beta Carotene - 5000 IU 2x per day
• Zinc - approximately 25 mg per day
• Alpha-Lipoic Acid - 300mg 1-2x per day

One thing we want you to remember is that while many of the discussed nutrients may be very effective antioxidants, there seems to be considerable overlap between some of their effects, making supplementing with a laundry list of vitamins and herbs redundant. Caution therefore should be exercised since each added supplement may increase the risk of nutrient-nutrient interactions that can either negate otherwise beneficial effects or even induce toxicity. Contrary to most advertising campaigns, all interactions are certainly not synergistic (or even additive), some may, in fact, be negative or toxic.

Much of the information contained in this article (and much more - including a complete list of 158 references) is discussed by the authors in their book chapter entitled Antioxidant Supplementation and Exercise. This chapter was published as Chapter 12 in Sports Supplements, a new supplement resource edited by Drs. Jose Antonio and Jeffery Stoudt. You can find this resource, as well as another supplement text that John has contributed to, Sports Supplement Encyclopedia, at SupplementBooks.com.

About the Author

John M Berardi is one of the world's foremost experts in the field of human performance and nutrition. His company, Science Link, provides unique and highly effective training, nutrition, and supplementation programs for high level athletes as well as recreational exercisers. John is a prolific author and a sought after speaker and consultant. Visit www.johnberardi.com for more information about John and his team. Also, check out his new DVD entitled No Nonsense Nutrition:

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