Most of the creatine in the body is found in muscle, where it exists primarily as creatine phosphate. When muscular work is performed, creatine phosphate provides the energy through hydrolysis of its "high-energy" phosphate bond, forming creatine with transferal of the phosphate to form an ATP. The reaction is reversible and catalyzed by the enzyme ATP-creatine transphosphorylase (also known as creatine phosphokinase).
The original pathways of creatine synthesis from amino acid precursors were defined by Bloch and Schoenheimer in an elegant series of experiments using 15N-labeled compounds (35). Creatine is synthesized outside muscle in a two-step process (Fig 2.5). The first step occurs in the kidney and involves transfer of the guanidino group of arginine onto the amino group of glycine to form ornithine and guanidinoacetate. Methylation of the guanidinoacetate occurs in the liver via S-adenosylmethionine to create creatine. Although glycine donates a nitrogen and carbon backbone to creatine, arginine must be available to provide the guanidino group, as well as methionine to donate the methyl group. Creatine is then transferred to muscle where it is phosphorylated. When creatine phosphate is hydrolyzed to creatine in muscle, most of the creatine is rephosphorylated when ATP requirements are reduced, to restore the creatine phosphate supply. However, some of the muscle creatine pool is continually dehydrated by a nonenzymatic process forming creatinine. Creatinine is not retained by muscle but is released into body water, removed by the kidney from blood, and excreted into urine (36).
Figure 2.5. Synthesis of creatine and creatinine. Creatine is synthesized in the liver from guanidinoacetic acid synthesized in the kidney. Creatine taken up by muscle is primarily converted to phosphocreatine. Although there is some, limited direct dehydration of creatine directly to creatinine, most creatinine comes from dehydration of phosphocreatine. Creatinine is rapidly filtered by the kidney into urine.
The daily rate of creatinine formation is remarkably constant (»1.7% of the total creatine pool per day) and dependent upon the size of the creatine/creatine-phosphate pool, which is proportional to muscle mass (37). Thus, daily urinary output of creatinine has been used as a measure of total muscle mass in the body. Urinary creatinine excretion increases within a few days after a dietary creatine load, and several more days are required after removal of creatine from the diet before urinary creatinine excretion returns to baseline, indicating that creatine in the diet per se affects creatinine production ( 38). Therefore, consumption of creatine and creatinine in meat-containing foods increases urinary creatinine measurements. Although urinary creatinine measurements have been used primarily to estimate the adequacy of 24-hour urine collections, with adequate control of food composition and intake, creatinine excretion measurements are useful and accurate indices of body muscle mass (39, 40), especially when the alternatives are much more difficult and expensive radiometric approaches.
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