Simulation of ATP metabolism in cardiac excitation–contraction coupling

Matsuoka, Satoshi; Sarai, Nobuaki; Jo, Hikari; Noma, Akinori

doi:10.1016/j.pbiomolbio.2004.01.006

Cited by 67 publications

(49 citation statements)

References 22 publications

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“…We also modeled two ATP-sensi- tive ion channels: the L-type Ca 2+ channel and the ATP-sensitive K + channel. At the steady state during stimulation of the model cell at 2.5 Hz, the concentrations of major metabolites ranged within the observed experimental measurements, suggesting that our estimations of ATP production and consumption during myocyte shortening are valid [26].…”

Section: A Simple Model Of Excitation-contraction-atp Metabolism Coupsupporting

confidence: 75%

“…4B. Cytoplasmic ATP concentration started to fall only after phosphocreatine had decreased to a min- [26]. B: NMR study of a whole rat heart modified from Kay et al [31].…”

Section: A Simple Model Of Excitation-contraction-atp Metabolism Coupmentioning

confidence: 98%

“…We developed a simple model of ATP metabolism in the cardiac myocyte [26]. In this model, a mathematical representation of the cell elements that are responsible for membrane excitation, the intracellular ion concentration changes, and contraction (such as the plasmalemmal ion channels and transporters and the sarcoplasmic reticulum) are essentially the same as our previous cardiac cell model (Kyoto model) [27,28].…”

Section: A Simple Model Of Excitation-contraction-atp Metabolism Coupmentioning

confidence: 99%

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An <i>In Silico</i> Study of Energy Metabolism in Cardiac Excitation-Contraction Coupling

Matsuoka

Sarai

et al. 2004

Jpn.J.Physiol

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developed a computer model of cardiac excitation-contraction coupling (Kyoto model) that includes the major processes of ATP production, such as oxidative phosphorylation that was originally developed for skeletal muscle by Korzeniewski and Zoladz [Biophys Chem 92: 17-34, 2001], creatine kinase, and adenylate kinase. In this review, we briefly summarize cardiac energy metabolism and discuss the regulation of mitochondrial ATP synthesis, using the Kyoto model. Energy balance is a key issue in cellular homeostasis, how it is achieved and what the consumers and producers of energy are. The problem of energy balance has been studied by the development of computer models of relatively simple cell types, such as the red blood cells and Escherichia coli (see review by Bassingthwaighte [1]). The next step in these studies is an in silico analysis of the energy homeodynamics of cardiac muscle, in which the major consumers of energy, such as muscle contraction and ion pumping, have been well studied. The basic principles required for modeling energy balance are summarized by Bassingthwaighte [1] and Jafri et al. [2]. Heart muscle receives energy from substrates and oxygen and delivers energy mainly for pumping blood around the systemic and pulmonary systems. The chemical energy that supports this cardiac work is derived from the hydrolysis of ATP. Therefore the heart is an energy transducer. An estimation based on myocardial oxygen consumption indicated that the human heart produces 35 kg of ATP in one day, which is more than 100 times its own weight and more than 10,000 times the amount of ATP it stores [3]. Thus the heart produces and uses ATP at an extremely high rate. Each step associated with ATP metabolism has been extensively studied. The relationship between ATP production and membrane excitation-contraction coupling, however, which is a main ATP-consuming process, is not yet fully understood because of complicated interactions and the lack of quantitative data in vivo. Computer simulation is a powerful tool with which to integrate experimental data and to solve the complicated interactions. But only a few computer models have been developed to deal with the cardiac excitation-contraction-energy metabolism coupling [4]. In this review we briefly summarize cardiac energy metabolism and describe our recent studies about cardiac ATP metabolism.

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Section: A Simple Model Of Excitation-contraction-atp Metabolism Coupsupporting

confidence: 75%

“…4B. Cytoplasmic ATP concentration started to fall only after phosphocreatine had decreased to a min- [26]. B: NMR study of a whole rat heart modified from Kay et al [31].…”

Section: A Simple Model Of Excitation-contraction-atp Metabolism Coupmentioning

confidence: 98%

Section: A Simple Model Of Excitation-contraction-atp Metabolism Coupmentioning

confidence: 99%

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An <i>In Silico</i> Study of Energy Metabolism in Cardiac Excitation-Contraction Coupling

Matsuoka

Sarai

et al. 2004

Jpn.J.Physiol

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“…For example, the widely used model of Korzeniewski and Zoladz [4][5][6] invokes an empirical linear relationship between the difference in pH across the mitochondrial inner membrane (matrix pH minus cytosol pH) and the magnitude of inner membrane potential. While the Korzeniewski model has been validated and verified based on a number of studies and is widely applied [7][8][9], the central empirical relationship between electrostatic potential and pH difference is not expected to apply under all conditions. For example, in the extensive study of isolated cardiac mitochondria published by Bose et al [10], this relationship is not obeyed.…”

Section: Introductionmentioning

confidence: 99%

A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

Beard¹

2005

PLoS Comp Biol

106

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A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at complexes I, III, and IV of the electron transport system, ATP synthesis at F 1 F 0 ATPase, substrate transporters including adenine nucleotide translocase and the phosphate-hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K þ /H þ antiporter and passive H þ and K þ permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphatedependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.

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“…The minimum requirements for such models might be the establishment of the steady-state condition and the implementation of mechanisms underlying the membrane excitation, the excitation-contraction coupling, the mechanical contraction, and the ATP metabolism. Here we used the Kyoto model [9], which successfully combined the Negroni-Lascano contraction model [10] with the membrane excitation and the ATP production of the oxidative phosphorylation model [11,12] based on the model structure created by D. Noble's group [13]. …”

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confidence: 99%

A Simulation Study to Rescue the Na+/Ca2+ Exchanger Knockout Mice

et al. 2006

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Abstract:The Na + /Ca 2+ exchanger (NCX) is the major Ca 2+ efflux system in cardiac myocytes, and thereby its global knockout is embryonically lethal. However, Henderson et al. (2004) found that mice with the cardiospecific knockout of NCX1 lived to adulthood. No adaptation was detected in expression levels of other proteins except for a 50% reduction in the L-type Ca 2+ current (I CaL ) as revealed in electrophysiological studies. To predict mechanisms of survival, we simulated cardiac myocyte activity in the absence of NCX using a mathematical model of guinea pig ventricular myocytes. The NCX knockout resulted in contracture of the model cell because of a rise in the cytoplasmic Ca 2+ ([Ca 2+ ] i ). However, up-regulation of the sarcolemmal Ca 2+ pump (PMCA) and/or down-regulation of I CaL enables steady rhythmic contractions even if NCX is totally excluded. The simulation predicted that the steady activities are maintained by a functional up-regulation of PMCA by about 2.3 times in addition to the down-regulation of I CaL to a half, as observed in the experiment. However, the model analysis predicted that the myocyte depending on PMCA for Ca 2+ extrusion is unstable against any changes in ionic fluxes and energetically unfavorable in comparison with the control. The reason for the instability is that the activity of PMCA driven by the ATP hydrolysis is hardly affected by changes in [Ca 2+ ] i , but NCX has a reversal potential in the middle level of the action potential and is immediately affected by the Ca 2+ flux via NCX itself. The source code of the model is available at http://www.sim-bio.org/.Key words: Na + /Ca 2+ exchanger, NCX1, sarcolemmal Ca 2+ pump.Cardiac excitation-contraction coupling is initiated by the influx of Ca 2+ through voltage-dependent Ca 2+ channels; it subsequently triggers Ca 2+ release from the sarcoplasmic reticulum (SR). To maintain stable excitationcontraction coupling, this Ca 2+ influx must be balanced by Ca 2+ efflux. The Na + /Ca 2+ exchanger (NCX) and ATP-dependent Ca 2+ pump (PMCA) are the two mechanisms that mediate Ca 2+ efflux via the plasma membrane, and the dominant role in cardiac myocytes of NCX1, an isoform of NCX, has been well documented [1,2]. Thus if NCX1 is removed, cardiac myocytes should become nonfunctional because of Ca 2+ overload. Therefore in our current understanding, it is almost inconceivable that myocardium could survive in the absence of NCX1. In fact, four laboratories have reported that a global knockout of the NCX1 is embryonically lethal [3][4][5][6]. However, surprisingly, Henderson et al. [7] reported that mice with a cardiospecific knockout of NCX1 lived to adulthood with only modestly reduced cardiac function. They could detect no adaptation in the expression levels of PMCA, the dihydropyridine receptor, ATP-dependent Ca 2+ pump on SR (SERCA), or calsequestrin as measured by both immunoblots and microarray analyses, but demonstrated that L-type Ca 2+ currents (I CaL ) were reduced by ~50% in the knockout mice.These findings raise severa...

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Simulation of ATP metabolism in cardiac excitation–contraction coupling

Cited by 67 publications

References 22 publications

An <i>In Silico</i> Study of Energy Metabolism in Cardiac Excitation-Contraction Coupling

An <i>In Silico</i> Study of Energy Metabolism in Cardiac Excitation-Contraction Coupling

A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

A Simulation Study to Rescue the Na+/Ca2+ Exchanger Knockout Mice

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