Creatine Metabolism in Skeletal Muscle

Abstract Creatine entry into the rat extensor digitorum longus muscle in vitro is inhibited by β-guanidinopropionic acid, β-guanidinoethanesulfonic acid, N-ethylguanidinoacetic acid, γ-guanidinobutyric acid, and guanidinoacetic acid (listed in order of effectiveness) but not by various amino acids or other compounds that lack an amidine group. β-Guanidinopropionic acid, when administered as 1% of the diet, also inhibits the entry of radioactively labeled creatine into skeletal muscle in vivo. In a study of the effects of three of the inhibitory compounds on the kinetics of creatine entry into the extensor digitorum longus muscle in vitro, each was found to compete with creatine for interaction with the transport site. From this study the Km and Vmax of creatine entry are 0.5 mm and 0.6 mmole per liter of intracellular water per hour, respectively; and the Ki values are 0.2 mm for β-guanidinopropionic acid, 1.0 mm for N-ethylguanidinoacetic acid, and 3.0 mm for guanidinoacetic acid. In a complementary study, β-guanidinopropionic acid was found to enter the extensor digitorum longus muscle by a saturable process with a Km of 0.2 mm and a Vmax of 0.6 mmole per liter of intracellular water per hour. Further, β-guanidinopropionic acid entry is competitively inhibited by creatine (Ki, 0.6 mm) and by guanidinoacetic acid (Ki, 3.3 mm). These data are evidence that creatine enters skeletal muscle via a novel transport site specifically adapted to interact with an amidine group.