Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function |
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Authors: | R Guzun N Timohhina K Tepp M Gonzalez-Granillo I Shevchuk V Chekulayev A V Kuznetsov T Kaambre V A Saks |
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Institution: | (1) Laboratory of Fundamental and Applied Bioenergetics, INSERM U884, Joseph Fourier University, 2280, Rue de la Piscine, BP53X-38041 Grenoble Cedex 9, France;(2) Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia;(3) Cardiac Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria; |
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Abstract: | Physiological role of creatine (Cr) became first evident in the experiments of Belitzer and Tsybakova in 1939, who showed
that oxygen consumption in a well-washed skeletal muscle homogenate increases strongly in the presence of creatine and with
this results in phosphocreatine (PCr) production with PCr/O2 ratio of about 5–6. This was the beginning of quantitative analysis in bioenergetics. It was also observed in many physiological
experiments that the contractile force changes in parallel with the alteration in the PCr content. On the other hand, it was
shown that when heart function is governed by Frank–Starling law, work performance and oxygen consumption rate increase in
parallel without any changes in PCr and ATP tissue contents (metabolic homeostasis). Studies of cellular mechanisms of all
these important phenomena helped in shaping new approach to bioenergetics, Molecular System Bioenergetics, a part of Systems
Biology. This approach takes into consideration intracellular interactions that lead to novel mechanisms of regulation of
energy fluxes. In particular, interactions between mitochondria and cytoskeleton resulting in selective restriction of permeability
of outer mitochondrial membrane anion channel (VDAC) for adenine nucleotides and thus their recycling in mitochondria coupled
to effective synthesis of PCr by mitochondrial creatine kinase, MtCK. Therefore, Cr concentration and the PCr/Cr ratio became
important kinetic parameters in the regulation of respiration and energy fluxes in muscle cells. Decrease in the intracellular
contents of Cr and PCr results in a hypodynamic state of muscle and muscle pathology. Many experimental studies have revealed
that PCr may play two important roles in the regulation of muscle energetics: first by maintaining local ATP pools via compartmentalized
creatine kinase reactions, and secondly by stabilizing cellular membranes due to electrostatic interactions with phospholipids.
The second mechanism decreases the production of lysophosphoglycerides in hypoxic heart, protects the cardiac cells sarcolemma
against ischemic damage, decreases the frequency of arrhythmias and increases the post-ischemic recovery of contractile function.
PCr is used as a pharmacological product Neoton in cardiac surgery as one of the components of cardioplegic solutions for
protection of the heart against intraoperational injury and injected intravenously in acute myocardial ischemic conditions
for improving the hemodynamic response and clinical conditions of patients with heart failure. |
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