The Evolution of Creatine

Those who have read my articles for a long time — or even a short time — know that much of the ink that fills their pages is dedicated to busting myths and "broscience." Without question, there are ample myths and nonsense in bodybuilding and fitness, and supplements are no exception. Creatine in particular has been shrouded in myths, half-truths, and, in some cases, outright lies. This article will break down the history of creatine and how it works, and help you decide if it's right for you.

THE BASICS
Let’s introduce you to creatine at its most basic level: Creatine is a nitrogen-containing organic acid made from a combination of three amino acids: glycine, methionine, and arginine. Creatine is found in signifi cant quantities in meats such as beef and fi sh. In humans, approximately 95 percent of creatine is stored in skeletal muscle, where around 60 to 65 percent of it exists as creatine phosphate and the rest exists as free creatine. Creatine concentrations in muscle seem to vary between individuals and may be infl uenced by factors such as age and diet, with vegetarians having lower levels of creatine than people who eat meats that contain higher levels of creatine.

Creatine phosphate is a major phosphate donor for adenosine
triphosphate (ATP) regeneration for adenosine diphosphate (ADP). ATP is the major energy currency for powering cellular processes. When your body oxidizes carbs, protein, or fat, the main reason is to produce ATP. ATP provides this energy for cellular processes by hydrolyzing a phosphate group.

When a phosphate group is hydrolyzed, energy is given off in the form of heat, and this energy is used to drive whatever process is being performed—for example, muscle contraction. This hydrolysis produces a single phosphate molecule and a molecule of ADP. The reaction is as follows: ATP (hydrolysis) Ð ADP + energy. ADP by itself doesn’t really power any reactions, so to continue a cellular process such as muscular contraction, you must regenerate ATP by converting ADP back into ATP through phosphate donation. Now this is where creatine comes into play. During sustained activity such as exercise, ATP can be depleted faster than can be replenished through typical metabolism. During these situations, creatine phosphate can donate its phosphate group to the ADP to re-form ATP! Thus, creatine improves energy production by acting as a phosphate donor to regenerate ATP from ADP.

EXERCISE PERFORMANCE
Those are the basics of cellular creatine biochemistry, but how does creatine supplementation play into this? Well, creatine supplementation has been shown to significantly increase concentrations of creatine phosphate in muscle tissue. The enhancement of creatine phosphate stores in muscle tissue led researchers in the early ‘90s to examine whether creatine could impact exercise performance since it does act as a phosphate donor and thus many researchers theorized that increasing muscle creatine concentrations may improve exercise performance. While the impact of creatine on aerobic endurance exercise performance has been disappointing, several studies have demonstrated that creatine supplementation improves exercise performance during high-intensity, anaerobic exercise such as sprinting. This improvement in performance is presumed to be through enhanced ATP synthesis during exercise, and it led scientists to examine if creatine could affect performance outcomes during resistance exercise. Dr. Richard Kreider and his team demonstrated that creatine improved total lifting volume in subjectsperforming bench press, squats, and power cleans. Further research has demonstrated that creatine supplementation can improve absolute strength, power, reps performed, and fatigue resistance during high-intensity weight-training programs.

BODY COMPOSITION AND MUSCLE MASS
Though these results are obviously great for powerlifters, sprinters, and other athletes concerned with performance, what application is there for bodybuilders? Bodybuilders typically only care about performance if it affects the bottom line of muscle gain. Presumably, through enhancing, strength, volume, and fatigue resistance, creatine could enhance total overload achieved during resistance-training sessions and thus lead to more overall hypertrophy. More importantly, however, it appears that creatine in and of itself is anabolic. Several studies have demonstrated that creatine supplementation enhances body mass, body composition, muscle mass, and lean body mass.

These positive results on mass and body composition seem to be influenced by several mechanisms. As stated previously, creatine improves resistance-exercise performance, which may enhance the growth response to training. Independent of the training adaptations to creatine, however, supplementation independently appears to activate hypertrophic signaling in muscle through a few different mechanisms. Many “experts” often suggest that the increase in body mass is due to increased fl uid retention associated with creatine supplementation. While it’s true that total body fluid increases with creatine supplementation, the percentage of total body water is unaffected. Thus, the gains in lean body mass associated with creatine intake seem to be from an increase in muscle fiber size, and the increase in water only occurs to compensate for the increased fi ber size. This is in accordance with data from Dr. Darren Willoughby, who demonstrated that creatine supplementation increased myofibrillar protein and the expression of myosin heavy chain, a large myofibrillar protein that is critical for muscular function and contraction. For those broscientists out there who say, “I don’t care about studies—I care about results,” one look at Dr. Willoughby is all you’d need to convince you to down creatine by the bucket, as the man is as thick as a brick house! He’s definitely a professor who practices what he preaches! 

In addition to the direct effects of creatine on muscle fiber size, supplementation has also been demonstrated to increase satellite cell and myonuclei content in muscle. To put it in basic terms, satellite cell and myonuclei number are very strong predictors of maximum muscle size. Satellite cells are undifferentiated “dormant” muscle fibers. In response to training, these cells become activated and can fuse to muscle fi bers and augment their size and donate their myonuclei to the muscle cell. Myonuclei are important because to maximize long-term muscle growth potential, you must maximize the number of myonuclei in muscle tissue. Each myonucleus controls muscle protein synthesis over a defined area of the muscle cell, so the more myonuclei you have, the greater the amount of muscle you can synthesize. Think of it like cell phone towers: You couldn’t provide cell phone coverage effectively to the entire world with just one cell phone tower. To maximize the signal coverage, you must increase the number of cell towers because each tower only has a certain range of coverage. To maximize muscle growth, you must maximize the number of myonuclei so that they can direct muscle growth over a greater overall area. In this way, creatine aids not only in short-term muscle growth but possibly also in long-term maximum muscle potential!

Finally, creatine may aid in lean mass accrual by improving recovery between sessions of exercise. Recently, it has been demonstrated that creatine supplementation could attenuate the strength decline induced by eccentric exercise and also decrease markers of muscle damage. By decreasing muscle damage and decreasing the time needed to recover between exercise sessions, creatine may improve the overall hypertrophic response to an exercise protocol by improving the effectiveness and frequency of training sessions.

RESPONDERS AND NON RESPONDERS
Not every study has supported creatine use, however. In fact, some studies have showed little or no benefit from creatine supplementation. This has led some researchers to theorize that there may be creatine “responders” and “non-responders.” This actually seems to be supported by scientific literature. Specifi- cally, people who have higher endogenous levels of creatine to begin with benefit less from creatine supplementation than those individuals who have low concentrations of creatine in muscle. Therefore, people who have lower levels of creatine in muscle will benefi t the most from supplementation. People who have naturally high levels of creatine in muscle may not respond as well.

PROPER DOSING
Typical dosing of creatine follows a 4- to 6-day loading period at 20 grams of creatine per day, followed by a maintenance period of 2 to 5 grams per day thereafter, which is sufficient to maximize intramuscular stores of creatine. Alternatively, ingesting 3 grams of creatine per day has also been shown to result in similar intramuscular creatine levels, although at a slower rate. Thus, it appears that loading is not needed to experience the long-term benefits of creatine; however, it will take longer to achieve the maximal gains of creatine using a steady 3-gram per day approach (28 days) compared to using a loading protocol (6 days), though it may be more cost effective.

CREATINE CYCLING
Many “experts” have suggested that creatine be cycled. Their reasoning is typically based on the observation that certain compounds such as anabolic steroids muscle be cycled to prevent decreased sensitivity and increased side effects to these compounds. Creatine, however, has been demonstrated to be very safe with no documented side effects. Some scientifi c rationale for maintaining sensitivity to creatine supplementation has been shown in the scientific literature through studies in rats demonstrating a decrease in creatine transporter content in muscle after long-term supplementation with creatine. Research has failed to validate these results in humans, however; Dr. Mark Tarnopolsky and his team demonstrated that creatine supplementation did not affect the expression or muscle content of the creatine transporter in muscle in young or elderly people. Because of the lack of evidence in humans, there is no reason at this time to suggest that cycling creatine is beneficial.

SYNERGISM WITH OTHER SUPPLEMENTS
Combining creatine with other supplements was popularized in the ‘90s when Dr. Green and his research team demonstrated that combining creatine with 93 grams of dextrose could enhance the uptake of creatine into muscle cells. This led to the popularization of combining creatine with large amounts of simple sugars to augment creatine uptake. Many people raised concerns about such a large sugar intake causing possible unfavorable health and body composition outcomes. Later research showed that the same effect could be achieved with much lower carbohydrate content than demonstrated by Green. Additionally, it has also been demonstrated that combining creatine with protein and carbohydrate with creatine at approximately 50 grams apiece could produce the same benefits. Additionally, combining creatine with alpha lipoic acid (1000 milligrams) has been demonstrated to enhance creatine stores compared to creatine supplementation alone. Creatine has also been shown to have a synergistic effect on lean body mass and performance when combined with HMB (3 grams per day) and beta-alanine (6 grams per day). Therefore, it may be optimal to consume creatine with an equal combination of protein and carbohydrate as well as 1000 milligrams of alpha lipoic acid to maximize creatine retention without excessive dietary carbohydrate intake. To further augment the effects of creatine on muscle mass and strength, users may also wish to add HMB and beta-alanine as well.

REINVENTING THE WHEEL?
Almost all studies showing benefits to creatine supplementation
use creatine monohydrate. It’s the tried and true form of creatine. Unfortunately, it’s also not very sexy or marketable for many supplement companies. Therefore, many companies come out with new forms of creatine constantly, purporting them to be more effective than creatine monohydrate with fewer side effects, such as water retention. As already mentioned, creatine has no side effects and doesn’t increase the percentage of body water, so those claims are bunk. One of the most popular alternative forms of creatine is creatine ethyl ester (CEE). CEE is claimed to be more readily absorbed with enhanced benefits compared to creatine monohydrate. However, these claims have been shown to be inaccurate, as CEE actually is less effective than monohydrate at increasing muscle concentrations of creatine, muscle mass, strength, and power. This may be due to increased CEE conversion to creatinine, the waste product of creatine. More recently, buffered creatine has been purported to be superior to creatine monohydrate, the reasoning being that providing a buffer with creatine will reduce its degradation during digestion by preventing acid-induced degradation. However, a recent review of the literature by experts in creatine dismissed this claim, stating that “studies have indicated that creatine monohydrate is not degraded during normal digestion and that nearly 99 percent of orally ingested creatine monohydrate is taken up by muscle or excreted in urine”—meaning that almost all creatine monohydrate is absorbed! Furthermore, the researchers emphasized that “there is little to no evidence that any of the newer forms of creatine are more effective or safer than creatine monohydrate whether ingested alone and/or in combination with other nutrients.” The answer is clear: Creatine monohydrate has been demonstrated to be safe.

SAFETY
Creatine’s safety has been the subject of scrutiny since it first hit the market. Several claims about creatine possibly harming the kidneys and liver were made by the mainstream media and researchers, the reasoning being that creatinine, the degradation
product of creatine metabolism, must be excreted by the kidneys. Researchers hypothesized that this could place an extra burden on the kidneys, and this led to creatine being blamed for a few acute renal failures in people supplementing with it. However, in most case studies, people experiencing side effects from creatine were taking large doses well above the recommended dosages for prolonged periods of time (greater than 20 grams a day for several weeks). Several subsequent studies concerning the effects of creatine supplementation of renal function demonstrated quite clearly that creatine monohydrate had no deleterious effects on healthy kidneys. Even so, it has been suggested that people with preexisting kidney problems avoid creatine, and while there are no studies in humans concerning creatine supplementation in people with already-compromised kidney function, a study by Dr. Taes examining the effects of creatine supplementation in rats with renal failure demonstrated that creatine did not exacerbate the disease. I’m in no way suggesting that people with poor kidney function should use creatine. Yet still, it has been clearly demonstrated that the concerns with creatine safety in regards to kidney function have been drastically overblown. Creatine has also been demonstrated to have no deleterious effects on the liver in addition to being safe for the kidneys.

Another concern of creatine supplementation that has been raised is the issue of creatine possibly causing dehydration due to its effect of increasing total body water. These concerns were widespread in the late 1990s and early 2000s; however, subsequent research studies showed conclusively that creatine supplementation did not increase the incidence of dehydration or cramping in people supplementing with creatine.

Finally, a claim by the French Food Sanitary and Safety Agency concerned many people a few years ago when it speculated that creatine supplementation may increase the production of heterocyclic amines, placing the kidneys at risk for elimination of these compounds. Even if there is a small increase in the production of these compounds, it does not affect kidney function.
Unfortunately, because of the effectiveness and popularity of creatine, it frequently has become a target for irresponsible media or organizations looking to generate buzz and creatine a controversy. The reality is that research has shown creatine supplementation to be perfectly safe when used within the recommended dosing guidelines.

CONCLUSION
In a supplement world filled with empty promises, misinformation, and half-truths, creatine is the real deal! It will work best for those who have already-low muscular concentrations of creatine. If you’re already blessed with really high muscular levels of creatine to begin with, it may not do a whole lot for you, however, since you’re already likely getting all the benefits! Make sure you don’t fall into marketing hype, and stick with the tried and true forms of creatine and dosing protocols.

Dr. Layne Norton is a pro natural bodybuilder and pro powerlifter. He earned his PhD in Nutritional Sciences with his thesis emphasis in muscle protein metabolism. He owns BioLayne LLC which offers nutrition and training consultations for bodybuilders, powerlifters, and weightlifting enthusiasts. To learn more about Layne and the services he offers, visit his website at: www.biolayne.com