The Creatine Secret – Part 1: Methylation Muscle

August 2005


1- Featured Article: The Creatine Secret-Part 1: Methylation Muscle

There is a little known aspect of creatine supplementation that is rarely, if ever, mentioned in the popular media. And, although apparently tangential to the most renowned of creatine’s effects, this relatively unheard of benefit of creatine supplementation can profoundly influence your ability to build muscle and to sustain a long and productive life. Indeed, this aspect of creatine supplementation can be truly classified as “anti-aging”. Today’s Creatine Newsletter will reveal the inner workings of this fundamental, yet relatively unheard of, biochemical pathway. Most importantly, this article will teach you some tricks to make this anabolic mechanism work in your favor with simple creatine and B vitamin supplementation.

Don’t miss out on future articles! Sign up and get the latest posts straight to your e-mail inbox or RSS reader.

This Month’s Featured Article:

The Creatine Secret-Part 1: Methylation Muscle

by A. Franco, PhD

Setting the Stage for Muscle Growth

It is a safe bet that most athletes never stop and think about their “methylation status”. Ironically, most athletes do spend huge amounts of mental energy scheming of ways of peaking their “anabolic status” in hopes of stimulating muscle growth. In truth, however, methylation and anabolism are inextricably linked processes. Figuratively speaking, methylation sets the stage on which anabolism is played out.

What is Methylation?

Without a doubt, methylation is one of the most commonly employed forms of cellular regulation. Estimates are that the body performs this indispensable process billions of times each second just to maintain life. Without going into too much detail, methylation is the attachment of a methyl group (CH3) to a biomolecule. And, although seemingly insignificant in complexity, this process can profoundly influence your ability to build new muscle tissue as well as to offset the decline in physical and mental capacities that typically accompany aging. The scope of this biochemical process is (in all honesty) all encompassing. Methylation is applied at the levels of our genes as well as is responsible for functionalizing many known growth factors, hormones, neurotransmitters, metabolic mediators and structural components of the cell. Indeed, life itself would not be possible without methylation, much less muscle growth. For an athlete there is no room for compromises in methylation capacity.

How does Creatine Influence Methylation?

A small sampling of the important molecules activated by a methylation reaction include adrenaline, carnitine, DNA, the polyamine growth regulators (putrescine, spermidine and spermine) and, of course, creatine. In fact, the synthesis of creatine is the single greatest drain of the body’s methyl reserves, consuming over 70% of the body’s entire supply. Furthermore, given that the body’s methyl reserves are limited in size, creatine synthesis alone could potentially create a state of methyl-deficiency. In a physiological sense, we have three principal options: (1) increase the size of the body’s methyl reserves; (2) increase the recycling rate of the body’s methyl reserves; or (3) create a scenario where the body no longer needs to synthesize creatine; that is, provide all the creatine the body needs through the diet. In this respect, athletes who supplement with creatine monohydrate are in fact, putting this third scenario into play, essentially sparring their methyl reserves and making more methyl groups available for the activation and synthesis other extremely important cellular targets.

Author’s Note: It is my personal belief that many of the “mysterious benefits” often attributed to creatine supplementation, but lacking full explanations, have to do with its ability to increase the body’s capacity to methylate important cellular targets, including our genes and essential anabolic modulators.

Simply Increasing Methyl Intake is the Wrong Approach

The body stores methyl groups in the form of a molecule known as S-AdenosylMethionine, or SAM. SAM is a derivative of the essential amino acid, methionine. The problem is, however, that the byproduct of SAM utilization (de-methylation) is a new molecule known as homocysteine. And, homocyteine is real bad news for our overall health and emotional well-being. Elevated homocysteine levels have been implicated in the development of Down’s syndrome, Parkinson’s disease, Alzheimer’s disease, stroke, dementia, coronary heart disease, vascular disease, anemias, renal disease and hepatic disease. Therefore, simply increasing our methionine intake (creating a surplus of SAM to be potentially converted into homocysteine), without taking into consideration the process of reconverting homocysteine into SAM, is a very dangerous physiological scenario. Therefore, although methionine intake is imperative in sustaining the methylation reactions that are necessary for life, not disposing of the homocysteine created from methionine consumption is counterproductive to health.

Homocysteine and Sex!

The elevated levels of homocysteine in the blood stream are highly indicative of the chances of developing several human disorders. For instance, serum homocysteine levels are typically 1.5 microMolar higher in men than women, ultimately translating into a 15% greater risk of cardiovascular disease in males. The source of this disparity is the significantly larger amounts of muscle mass in men, necessitating greater amounts of endogenous creatine synthesis to meet muscular requirements; remember, creatine synthesis produces homocysteine. Creatine supplementation may hence represent an effective strategy to reduce serum homocysteine levels in males (or anyone) at high risk of developing cardiovascular disease.

Complete Reliance on Creatine Synthesis Also Elevates Serum Homocysteine Levels

Oddly, just as over-consumption of methionine-rich food sources might elevate serum homocysteine levels, so does their under-consumption. This seeming paradox stems from the fact that meat and fish, as well as being good sources of methionine, are also rich sources of creatine. Therefore, under-consuming sources of dietary creatine, increases the need for creatine synthesis and consequently, increases the production of homocysteine.

Essential B-Vitamins Reduce Serum Homocysteine Levels

The principal mechanism whereby the body rids itself of homocysteine involves two B-vitamins, folate and B12 (shown in red in figure). Originally, folate received its name from folium, the Latin word for leaf. Nearly 70 years ago (1941) an American scientist named Esmond Snell isolated a “growth factor” from spinach (leafs) that promoted cell division and growth. In truth, however, the life-sustaining properties of folate had been unwittingly demonstrated a few years before Snell’s isolation. In 1938 Robert Stokstad identified a component from yeast that was effective at treating megaloblastic anemia. Stokstad named his healthful agent “Factor U”. Subsequently, exact chemical characterization demonstrated Snell’s folate and Stokstad’s mysterious Factor U to be one in the same.

Nearly four tons of spinach leafs were required by Snell to isolate enough folate for initial biochemical characterization, indicating that plants contain only scant amounts of folate. The richest natural sources of folate are in fact, of animal origin, in particular, the liver. B12 (cobalamin) is the other B-vitamin used to neutralize homocysteine and is similarly enriched in animal products, especially milk and cheese.

It is now known that folate and B12 act collectively by re-methylating homocysteine, thereby recreating methionine, which is then quickly converted into SAM by the cell. Therefore, supplementing with these important B vitamins has two important consequences: (1) it replenishes the body’s SAM reserves; and (2) it removals potentially dangerous homocysteine from the blood stream. In essence, folate and vitamin B12 are the body’s most important methionine recyclers.

Creatine synthesis produces homocysteine that needs to be removed from the blood stream (before harm is done to the organism) with the assistance of the B vitamins, folate and B12. Importantly, creatine supplementation, by circumventing the need for creatine synthesis, effectively spars the body’s methyl reserves and diminishes the production of homocysteine.

Take a closer look at the creatine synthesis here:

In this unique sense, vegans represent a worst-case scenario. First, animal proteins are the richest natural sources of creatine. And, as mentioned previously, dietary creatine deficiency results in creatine synthesis presiding over all else. Complete reliance on creatine synthesis, in turn, results in homocysteine levels rising dangerously. Secondly, animal proteins are also very good sources of folate and vitamin B12. These B vitamin are needed to re-create methionine (SAM) from homocysteine, effectively completing the methylation cycle. Therefore, the dual absence of creatine and essential B vitamins from the diet creates a potentially very dangerous scenario that would completely undermine muscle growth and recovery.

Maximizing Methylation Status for Optimal Anabolism

Frankly, a suboptimal methylation status will put the brakes on muscle growth! In this respect, combining creatine supplementation with targeted vitamin B intervention will doubly amplify muscle anabolics by maximizing the body’s methyl reserves while simultaneously providing a greater training stimulus for muscle growth.

Essential B vitamins will also assist in the final stage of creatine synthesis by increasing the availability of SAM. This effect of B vitamins, in turn, means that lower doses of creatine can be taken to produce the same benefits. This strategy (see guide, below) is highly recommended for the elderly, persons wishing to alleviate the symptoms associated with taking large amounts of creatine as well as anyone predisposed to renal dysfunction.

Doses of Folic Acid & Vitamin B12

Surprisingly, the folate found within natural sources is not readily available to the body, as it exists in large conglomerations of many folates bound by glutamate residues (polyglutamates). These polyglutamates must first be enzymatically cleaved into individual folates (monoglutamates) before they can be absorbed into the blood stream. This process is inefficient, however, reducing the bioavailability of natural folates by as much as 25% to 50%. Here in lies the major advantage of synthetically derived folate, or folic acid; folic acid is more easily absorbed by the body.

Based on scientific studies, to maintain optimal methylation levels an average person in relatively good health should consume between 500-1000 micrograms of folic acid and 100-500 micrograms of vitamin B12 each day.

The requirements for an athlete, on the other hand, will be substantially greater, possibly several-fold. Strenuous exercise severely damages muscle, which then needs to be repaired and rebuilt (to a greater degree) during periods of rest; this is the basic paradigm of strength training. It is thus essential that methylation capacity be sufficiently high during moments of recovery from exercise as to support tissue growth and prevent the loss of existing muscle.

Giving urgency to this caveat, a modest 10% loss in muscle mass produces a 30% loss in strength. Translating, a 70 kilogram (154 pounds) athlete who loses 0.7 kilograms (1.5 pounds) of weight because of overtraining, can expect to drop 5-7 kilograms (11-15 pounds) in the bench press, depending on his/her single repetition maximum!

Folate, Cancer & Aging

At the root of all life are nucleic acids, the DNA that comprises our genes. Our genes code for every component that the cell will ever express. That is, the selection of which genes are read will ultimately determine a muscle cell from a brain cell, an active cell from a dormant cell, a growing cell from a degenerating cell, or a young cell from an old cell. In brief, our genes decide who, and what, we are at each point in our existence.

Moreover, methylation determines which genes are read and eventually manifested in the cell. Under-methylation (hypo-methylation) switches the pattern of gene expression to one more commonly associated with cancer. For instance, hypo-methylation of the tumor suppressor gene, p53, leads to a two-fold increase in the incidence of bronchial cancer in male smokers; cigarette smoke severely compromises methylation by degrading cellular folate reserves. Folate deficiency predisposes us to cancer and has been associated with the expression of carcinomas of the colon-rectum, lungs, cervix, esophagus pancreas and breast.

DNA methylation also influences chromosome structure, the cell’s ability to repair damaged DNA as well as overall genomic stability. Expectedly, hypo-methylation also results in inefficient replication of DNA, breaks in the chromosomal linear structure and inefficient repair of damaged chromosomes. Folate-based methylation thus protects our genes from spontaneous mutations and chromosome damage that could lead to cancer and cell death.

An age-related decline in methylation capacity is thought to instigate senescence and the loss of physical capacity in the elderly. Folate-deficiency, producing a premature state of hypo-methylyation, may accelerate the normal aging process.

Folate supplementation will thus slow the progressive loss in mental and physical capacities associated with aging as well as protect against many age-related diseases, such as cancer.

Concluding Remarks

Methylation is necessary for cellular proliferation and survival, which, in turn, are the foundations for muscle anabolism. Therefore, optimizing your body’s methylation status is an essential first step in building muscle. And, by far, the best way to maximize your methyl reserves is by combining creatine and vitamin B supplementation, a powerful duo at replenishing the body’s methyl reserves and at priming muscle growth.

Next month we will talk about another vitamin B intervention that will improve an athlete’s antioxidant status. Employing this measure, in turn, will greatly augment an athlete’s ability to recover from intense exercise as well as further accentuate methylation status.

Scientific References

McCarty, M. F. (2001) Supplemental creatine may decrease serum homocysteine and abolish the homocysteine ‘gender gap’ by suppressing endogenous creatine synthesis. Medical Hypotheses, Volume 56 (1), pages 5-7.

Stead, L. M. et al. (2001) Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. American Journal of Physiology and Endocrinological Metabolism, Volume 281, pages E1095-E1100.

Taes, Y. E. C. et al. (2003) Creatine supplementation decreases homocysteine in an animal model of uremia. Kidney International, Volume 64, pages 1331–1337.

Share this article with your circle of friends: The Creatine Secret-Part 1: Methylation Muscle.

Still have questions about creatine? You'll probably find the answers in my ebook!

Creatine: a practical guide will teach you how to use creatine safely and effectively for greatest muscle growth. You'll learn: how to design your own personalized dosing protocol, what to eat (and what not to eat) and other methods to make the greatest muscle gains, at the lowest price. Also, find out whether expensive creatine formulations are really worth the money!

All for less than the cost of your monthly creatine!

More information