L-Arginine:GlycineAmidinoTransferase, the first of two enzymes used in the synthesis of creatine. This enzyme catalyzes the production of GuanidinoAcetic Acid (GAA) and ornithine from the chemical union of arginine and glycine.

The body normally defends itself from free radical damage with the help of antioxidants. Antioxidants are typically able to neutralize ROS as soon as they are produced. During moments of elevated oxygen consumption (for instance, exercise), however, the levels of ROS may increase to the point where they actually overrun the body’s normal antioxidant defenses, giving rise to a degenerative scenario known as oxidative stress. To combat oxidative stress the body produces its own battalion of antioxidants as well as obtains antioxidants from the diet. Glutathione is one of the most potent antioxidants that the body produces. Catalase, superoxide dismutase and glutathione peroxidase are examples of antioxidant enzyme complexes that the body manufactures. Examples of dietary antioxidants include vitamins A, C and E.

Read about the antioxidant properties of creatine at the following link.

A Greek term meaning to enhance physical performance. Often used to describe the physical benefits typically afforded creatine supplementation.

Free Radical
An chemically charged atom or molecular fragment due to an excess, or deficiency, of electrons. Free radicals seek, or release, electrons to achieve a more stable configuration, a process that can damage larger biologically important molecules within cells.

In cellular terms, the most damaging of free radicals are Reactive Oxygen Species, or ROS. During normal levels of activity, most of the oxygen consumed by cellular respiration is reduced to water; oxygen is the “O” in H2O. This process is not perfect, however, and a small amount of oxygen is inevitably converted into ROS. Most importantly, the rate at which ROS are produced increases in parallel with exercise intensity, i.e. with increasing oxygen consumption. This is a process known as Oxidative Stress.

ROS are notorious at destabilizing cellular membranes, ultimately giving rise to microscopic tears of the muscle surface. These tears allow the unabated entry of calcium into the cell, which in turn, triggers the activity of proteases, enzymes that degrade proteins, further damaging the membrane. The uncontrolled activity of proteases produces areas of muscle damage, known as necrosis, that can ultimately lead to the death of the cell.

Gyrate Atrophy
A disease of the eye (retina) characterized by progressive narrowing of the visual fields. This disease stems from a metabolic imbalance resulting in defective creatine synthesis. Another symptom of the disease is atrophy of fast muscle fibers, which might be expected since creatine influences primarily fast muscle fibers. Clinical studies conducted on patients with Gyrate Atrophy have demonstrated that creatine supplementation effectively alleviates the muscular symptoms of the disease, while the visual effects remain largely unchanged. This paradoxical finding is not entirely unexpected given the low permeability of the blood brain barrier to creatine and the low doses of creatine used in these studies. However, other than mild weight gain, the low doses of creatine monohydrate (1.5 – 2 grams/day) used in these studies produced no obvious side effects even when administered for periods of between 8-15 years.

A sulfur containing amino acid produced following the consumption of S-AdenosylMethionine (see next) during cellular methylation. In essence, homocysteine is a version of the essential amino acid, methionine, lacking its key methyl group. Homocysteine is normally removed from circulation via its recycling into methionine with the help of folate and vitamin B12.

Elevated serum homocysteine levels have been implicated in the development of aggressive vascular disease in the heart and central nervous system. An important recent finding is that creatine supplementation lowers serum homocysteine levels (Click here for details).

Methylation Reactions
A ubiquitous form of biochemical modification used in biology. Methylation involves the attachment a methyl group to a substrate via the actions of specialized enzymes collectively known as methyl-transferases. Some important examples of products of methylation include creatine, adrenaline, carnitine, melatonin, muscle proteins, neurotransmitters, blood lipids, growth factors, growth hormones, components of the cell membrane and nucleic acids (DNA and RNA). Frankly speaking, life itself would not be possible without methylation reactions.

Our principal sources of methy groups to support methylation reactions are methionine (the essential amino acid) and folate (the B-vitamin). Methionine is activated for methylation through its chemical union with Adenosine TriPhosphate (ATP) to produce S-AdenosylMethionine (SAM). Moreover, folate is a direct source of methy groups of the synthesis of our genetic material (DNA and RNA) as well as remethylates SAM once it is consumed by methylation.

The by-product of SAM consumption is homocysteine (see previous). Homocysteine, in turn, has been implicated in the development of several humans disorders. Folate, since it recreates SAM from homocysteine as well as supports other important methylation reactions in the body, is absolutely essential for overall good physical and mental health and normal development.

Methionine Metabolism and Homocysteine

The synthesis of creatine is the greatest single drain to our methyl reserves. In this respect, creatine supplementation, in bypassing the need for creatine synthesis, spares the body’s methyl reserves and heightens one’s methylation status.

Mitochondria are literally the furnaces of the cell, where the cell’s nutrients are combusted (oxidized) for the ultimate production of energy (ATP). In these cellular organelles the carbon skeletons of carbohydrates (glucose), proteins (amino acids) and fats (fatty acids) mix with oxygen to yield ATP, water and carbon dioxide.

Mitchondria evolved from once free-living ancient microbes (prokaryotes) that were able to utilize the oxygen present in the ancient atmosphere; in other words, they were aerobic. These aerobic microorganisms established a mutually beneficial partnership with anaerobes that were unable to neutralize the potentially toxic oxygen that was increasingly present in their environment – the outcome of this symbiotic relationship was higher organisms (eukaryotes) that are able to produce energy in the absence as well as with the assistance of oxygen.

Nitric Oxide
The first gas recognized as a biological second messenger, Nitric Oxide (NO) was originally characterized in the endothelium lining blood vessels where it was given the name Endothelium-Derived Relaxing Factor (EDRF) for its role in relaxing the smooth muscle cells that control the diameter of blood vessels; NO is a potent vasorelaxor. Since its initial characterization in the vascular endothelium, the cellular processes ascribed to the actions of NO have greatly increased in number. The physiological processes now believed to be under the control of NO include nerve-to-nerve communication, smooth muscle relaxation (for example, in the penis where it causes erection), sphincter control, heightening immune responses, reducing platelet aggregation in patients with high cholesterol and the release insulin from pancreatic beta cells. The insulinotropic attributes of NO confer to it an anabolic role.

NO is produced from the amino acid arginine by an enzyme known as NO synthase. Because of its involvement in NO synthesis, arginine is considered (by some) an anabolic amino acid. For analogous reasons, arginine is sometimes prescribed as a treatment for erectile dysfunction. Available evidence, however, leans either way (for and against) on these potential attributes of arginine supplementation.

Approximately 20-30% of the population shows only modest responses to creatine supplementation. These individuals have been coined “non-responders” by the creatine community. Although the precise reasons for all non-responders are not fully understood, several explanations have been offered. First, the appropriate exercise task must be examined to determine the true efficacy of creatine supplementation. Creatine’s effects are most noticeable during repeated bouts of strenuous exercise. Therefore, the effects of creatine would be less obvious, possibly even undetectable, if examined in the context of endurance sports. Secondly, you muscle creatine levels must increase by at least 20% for a clear difference in physical performance to be evident. Some non-responders may possess such naturally high creatine levels that a further increase in muscle creatine content of this magnitude is simply not possible. Thirdly, since exercise increases creatine absorption, supplementing outside the context of a regular exercise routine may not give detectable results. Lastly, it now appears that the muscles of some persons might require a little bit of assistance in taking up creatine from the blood stream. It is thus likely that most non-responders will convert to full-fledged responders provided with the appropriate supplementing regimen.

Creatine: A practical guide teaches how to most effectively combine exercise, nutrition and smart creatine use for explosive muscle growth and enhanced athletic performance.

Reactive Oxygen Species
see Free Radicals.

Type I Muscle Fibers
This muscle fiber class also goes by a variety of other names such as slow twitch, aerobic, oxidative, and red muscle fibers. In essence, slow muscle fibers are so named because they express a slower acting isoform of the contractile protein known as myosin. That is, slow muscle fibers contract slowly; contraction is the active force that underlies all muscle movement. Slow muscle fibers are also slower at producing energy, since they require the presence of oxygen to convert nutrient energy into ATP. The slower rate of energy produced by slow muscle fibers means that they are unable to reach the high levels of force generation typical of fast muscle fibers (see next). To support their elevated oxidative capacities, slow muscle fibers are fed by rich vascular beds, come equipped with many mitochondria (and associated oxidative enzymes) and contain large quantities of myoglobin. These characteristics make slow muscle fiber well adapted to extract a hydrocarbon’s (carbohydrates, fatty acids and deaminated amino acids) full allotment of ATP when oxygen is sufficiently available. The coloration of slow muscle fibers arises from the existence of heme (iron-containing) complexes in myoglobin, which, upon binding oxygen, turn red. Slow muscle fibers thus generate low levels of force, but are more resistant to fatigue. Since fatty acids are a major source of fuel for type I muscle fibers, endurance exercise burns fat.

Type II Muscle Fibers
This muscle class is also known as fast twitch, anaerobic, glycolytic or white. Type II muscle fibers express an isoform of myosin that is quicker at splitting ATP to liberate energy and, consequently, are more rapid at provoking contraction. Type II muscle fibers also contain greater quantities of anaerobic energy substrates, namely creatine, phosphocreatine (PCr) and glycogen.

Fast muscle fibers are commonly subdivided into two separate categories, Type IIa and Type IIb. Type IIb fibers are the proverbial fast twitch muscle fibers often made reference to in exercise physiology texts and are very well adapted for anaerobic (oxygen-independent) energy (ATP) production. Type IIb fibers, however, since they possess relatively few mitochondria, are not well suited to fully combust glucose in the presence of oxygen for the production of ATP (see above). Type IIb muscle fibers also contain relatively little myoglobin and hence lack the deep red coloration and oxygen storage capacity of type I muscle fibers. Because of their unique biochemical makeup, type IIb muscle fibers generate large forces, but fatigue rapidly. Glycogen is a major source of fuel for type IIb fibers. Type IIb muscle fibers are the muscle fibers that are most responsive to creatine supplementation.

Creatine: A practical guide discusses how to best optimize the effects of creatine supplementation.

Type IIa fibers are a hybrid class of muscle, possessing both type I and type IIb fiber characteristics. Type IIa fibers contain significant levels of creatine, phosphocreatine, glycogen and myoglobin. Type IIa also contain many mitochondria and express high levels of the enzymes used during cellular respiration. Consequently, type IIa fibers can generate large forces and are relatively resistant to fatigue. However, the force they generate will still be less than that of purely type IIb fibers and they are not as resistant to fatigue as purely type I fibers. Type IIa fibers are thus intermediate in contractile characteristics.

An increase in cell size (volume) as a result of the incorporation of an osmotically active particle (such as creatine) within the cell. In essence, water flows into the cell in an attempt to dilute the higher concentration of osmolyte held inside, effectively inflating the cell with water. In many cases cell volumization has been shown to possess secondary anabolic effects.

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