Jones AM, Wilkerson DP, Fulford J. Influence of dietary creatine supplementation on muscle phosphocreatine kinetics during knee-extensor exercise in humans. Am J Physiol Regul Integr Comp Physiol 296: R1078 -R1087, 2009. First published February 11, 2009 doi:10.1152/ajpregu.90896.2008.-We hypothesized that increasing skeletal muscle total creatine (Cr) content through dietary Cr supplementation would result in slower muscle phosphocreatine concentration ([PCr]) kinetics, as assessed using 31 P magnetic resonance spectroscopy, following the onset and offset of both moderateintensity (Mod) and heavy-intensity (Hvy) exercise. Seven healthy males (age 29 Ϯ 6 yr, mean Ϯ SD) completed a series of square-wave transitions to Mod and Hvy knee extensor exercise inside the bore of a 1.5-T superconducting magnet both before and after a 5-day period of Cr loading (4ϫ 5 g/day of creatine monohydrate). Cr supplementation resulted in an ϳ8% increase in the resting muscle oxygen uptake kinetics; respiratory control; creatine kinase; muscle energetics; 31 P magnetic resonance spectroscopy MEYER'S "ELECTRICAL ANALOG" model of respiratory control posits that the time constant () for the exponential fall in muscle phosphocreatine concentration ([PCr]) following the onset of muscle contractions is a function of the mitochondrial resistance and the metabolic capacitance (45). The model predicts that an increase in mitochondrial density will result in a shorter (that is, faster [PCr] kinetics) and that an increase in metabolic capacitance, determined predominantly by the muscle total creatine (Cr) content, will result in a longer (slower [PCr] kinetics). In keeping with this prediction, Meyer and colleagues reported that increased citrate synthase activity induced by endurance training resulted in faster [PCr] kinetics in rat muscle (49) and that depletion of the total Cr content of rat gastrocnemius muscle, achieved through 8 wk of feeding with the Cr analog -guanidinopropionic acid, resulted in significantly faster [PCr] (1,9,42,47). In an important recent study, Kindig et al. (35) reported that acute CK inhibition led to a significantly faster fall in intracellular PO 2 (equivalent in this model to a faster rise in V O 2 ) following the onset of contraction in isolated Xenopus myocytes. Moreover, Glancy et al. (16) demonstrated that the for oxygen consumption in isolated mitochondria was linearly related to the total Cr content in the incubation medium.Collectively, these data provide strong support for the notion that the for both muscle [PCr] and V O 2 conforms to a simple linear model of respiratory control, at least under the conditions of the experiments performed. In humans, however, data relating [PCr] and/or V O 2 kinetics to the muscle total Cr content are sparse. Francescato et al. (15) recently reported that intersubject differences in resting muscle [PCr] were positively correlated (r ϭ 0.71) with the for the fall in [PCr] during plantar flexion exercise in humans. However, the range of resting [PCr] values ...