The first tangible puzzle reflects Creatine (Cr) and Creatine Kinase System (CK). Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the Creatine Kinase system is associated with most of it. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr by itself and Cr analogs such as Cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. This said, one perceives it rational that ever since the discovery of Phosphorylcreatine (CP) in 1927 and particularly of its essential CK enzyme in 1934, research efforts focused mainly on biochemical, physiological, and pathological aspects of the CK reaction itself and on its involvement in “high-energy phosphate” metabolism of cells and tissues with high-energy demands. In contrast, Cr (from Greek kreas, flesh) metabolism of itself has attracted considerably less attention until 1972. Nevertheless, oral Cr ingestion has independently been introduced as ergogenic (quick energy supplier) aid in sports.
However, first Cr was used in sports as an overly ergogenic aid to the actively contracting striated muscle, mainly fast-twitch white myofibrils. At the same time independent observations has been reported on the simaltenuous increase under similar experimental condition in muscle protein. Then, a new era in Cr science has boldly declared itself.
The following important amino acids L-arginine, Glicine, and S-adenosil-L-methionine to yield guanidinoacetic acid, the immediate precursor of Cr after its methylation, are involved in biosynthesis of Cr in the body. The most part (up to 94%) of Cr is found in the muscular tissue. Yet muscle has virtually no Cr-synthesizing capacity, Cr has to be taken up from the blood against a large concentration gradient by a saturable, Na+ - and Cl-- -dependent Cr transporter that spans the plasma membrane. The daily demand for Cr is met either by intestinal absorption of dietary Cr or by de novo Cr biosynthesis. The first step of Cr biosynthesis probably occurs mainly in the kidney, whereas the liver is likely to be the principal organ accomplishing the subsequent methylation of guanidinoacetic acid to Cr. It is worthy to note that the detailed contribution of different organs (pancreas, kidney, liver, testicls) to total Cr synthesis is still rather unclear. The muscular Cr and CP are later nonenzymatically converted at an almost steady rate (approximately 2% of total Cr per day) to Crn, wich diffuses out of the cells and is excreted by the kidneys into the urine. The highest levels of Cr andCP are found in skeletal muscle, heart, spermatozoa, and photoreceptor cells of the retina. Intermediate levels are found in brain, brown adipose tissue, intestine, seminal vesicles, seminal vesicle fluid, endothelial cells, and macrophages. Resting type 2a and 2b skeletal muscle fibers (white fast twitch) contain around 33mM CP and 7mM C, whereas type 1 fibers (red slow) comprise about 16mM CP and 7mM Cr. Nevertheless, the concentration of total Cr seems to parallel the muscle glycolitic capacity in both muscle types. In serum and erythrocytes, as opposite extremes, Cr amounts to only 25-100uM and 270-400uM, respectively. An almost constant fraction of the body Cr (1.1% a day) and CP (2.6% a day) is converted nonenzymatically into Crn, giving a overall conversion rate for the total Cr pool (Cr and CP) of approximately 1.7% a day. Consequently, in a 70-kg man containing about 120g of total Cr, roughly 2g/day are converted into Crn, and have to be replaced by Cr from the diet or from de novo biosynthesis.