title: Similar mitochondrial activation kinetics in wild-type and creatine kinase-deficient fast-twitch muscle indicate significant Pi control of respiration.
abstract: Past simulations of oxidative ATP metabolism in skeletal muscle have predicted that elimination of the creatine kinase (CK) reaction should result in dramatically faster oxygen consumption dynamics during transitions in ATP turnover rate. This hypothesis was investigated. Oxygen consumption of fast-twitch (FT) muscle isolated from wild-type (WT) and transgenic mice deficient in the myoplasmic (M) and mitochondrial (Mi) CK isoforms (MiM CK(-/-)) were measured at 20°C at rest and during electrical stimulation. MiM CK(-/-) muscle oxygen consumption activation kinetics during a step change in contraction rate were 30% faster than WT (time constant 53 ± 3 vs. 69 ± 4 s, respectively; mean ± SE, n = 8 and 6, respectively). MiM CK(-/-) muscle oxygen consumption deactivation kinetics were 380% faster than WT (time constant 74 ± 4 s vs. 264 ± 4 s, respectively). Next, the experiments were simulated using a computational model of the oxidative ATP metabolic network in FT muscle featuring ADP and Pi feedback control of mitochondrial respiration (J. A. L. Jeneson, J. P. Schmitz, N. A. van den Broek, N. A. van Riel, P. A. Hilbers, K. Nicolay, J. J. Prompers. Am J Physiol Endocrinol Metab 297: E774-E784, 2009) that was reparameterized for 20°C. Elimination of Pi control via clamping of the mitochondrial Pi concentration at 10 mM reproduced past simulation results of dramatically faster kinetics in CK(-/-) muscle, while inclusion of Pi control qualitatively explained the experimental observations. On this basis, it was concluded that previous studies of the CK-deficient FT muscle phenotype underestimated the contribution of Pi to mitochondrial respiratory control.
authors: Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. j.a.l.jeneson@umcutrecht.nl
authors: Jeroen A L
authors: JA
authors: Jeneson
authors: Frank
authors: F
authors: ter Veld
authors: Joep P J
authors: JP
authors: Schmitz
authors: Ronald A
authors: RA
authors: Meyer
authors: Peter A J
authors: PA
authors: Hilbers
authors: Klaas
authors: K
authors: Nicolay
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D019069:Cell Respiration / Q000502:physiology; D052283:Creatine Kinase, MM Form / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000502:physiology*; D023421:Models, Animal; D008962:Models, Theoretical; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology*; D010641:Phenotype; D010710:Phosphates / Q000378:metabolism*
chemical_list: D010710:Phosphates; D000244:Adenosine Diphosphate; D052283:Creatine Kinase, MM Form