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Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function

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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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Acknowledgments

This work was supported INSERM, and by a grant from Agence Nationale de la Recherche, France, project ANR-07-BLAN-0086-01 and by grants N 7117 and 7823 from Estonian Science Foundation. The authors thank Irina Guzun for improving the English of this manuscript.

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  1. Laboratory of Fundamental and Applied Bioenergetics, INSERM U884, Joseph Fourier University, 2280, Rue de la Piscine, BP53X-38041, Grenoble Cedex 9, France

    R. Guzun, M. Gonzalez-Granillo & V. A. Saks

  2. Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia

    N. Timohhina, K. Tepp, I. Shevchuk, V. Chekulayev, T. Kaambre & V. A. Saks

  3. Cardiac Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria

    A. V. Kuznetsov

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Guzun, R., Timohhina, N., Tepp, K. et al. Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function. Amino Acids 40, 1333–1348 (2011). https://doi.org/10.1007/s00726-011-0854-x

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  • DOI: https://doi.org/10.1007/s00726-011-0854-x

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