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Kongas2007 - Creatine Kinase in energy metabolic signaling in muscle

ABSTRACT: Kongas2007 - Creatine Kinase in energy metabolic signaling in muscle This model is described in the article: Creatine kinase in energy metabolic signaling in muscle Olav Kongas and Johannes H. G. M. van Beek Available from Nature Precedings Abstract: There has been much debate on the mechanism of regulation of mitochondrial ATP synthesis to balance ATP consumption during changing cardiac workloads. A key role of creatine kinase (CK) isoenzymes in this regulation of oxidative phosphorylation and in intracellular energy transport had been proposed, but has in the mean time been disputed for many years. It was hypothesized that high-energy phosphorylgroups are obligatorily transferred via CK; this is termed the phosphocreatine shuttle. The other important role ascribed to the CK system is its ability to buffer ADP concentration in cytosol near sites of ATP hydrolysis. Almost all of the experiments to determine the role of CK had been done in the steady state, but recently the dynamic response of oxidative phosphorylation to quick changes in cytosolic ATP hydrolysis has been assessed at various levels of inhibition of CK. Steady state models of CK function in energy transfer existed but were unable to explain the dynamic response with CK inhibited. The aim of this study was to explain the mode of functioning of the CK system in heart, and in particular the role of different CK isoenzymes in the dynamic response to workload steps. For this purpose we used a mathematical model of cardiac muscle cell energy metabolism containing the kinetics of the key processes of energy production, consumption and transfer pathways. The model underscores that CK plays indeed a dual role in the cardiac cells. The buffering role of CK system is due to the activity of myofibrillar CK (MMCK) while the energy transfer role depends on the activity of mitochondrial CK (MiCK). We propose that this may lead to the differences in regulation mechanisms and energy transfer modes in species with relatively low MiCK activity such as rabbit in comparison with species with high MiCK activity such as rat. The model needed modification to explain the new type of experimental data on the dynamic response of the mitochondria. We submit that building a Virtual Muscle Cell is not possible without continuous experimental tests to improve the model. In close interaction with experiments we are developing a model for muscle energy metabolism and transport mediated by the creatine kinase isoforms which now already can explain many different types of experiments. The model has been designed according to the spirit of the paper. The list of rate in the appendix has been corrected as follow: d[ATP]/dt = (-Vhyd -Vmmck +Jatp) / Vcyt d[ADP]/dt = ( Vhyd +Vmmck +Jadp) / Vcyt d[PCr]/dt = ( Vmmck +Jpcr ) / Vcyt d[Cr]/dt = (-Vmmck +Jpcr ) / Vcyt d[Pi]/dt = ( Vhyd + Jpi ) / Vcyt d[ATPi]/dt = (+Vsyn -Vmick -Jatp) / Vims d[ADPi]/dt = (-Vsyn +Vmick -Jadp) / Vims d[PCri]/dt = ( Vmick -Jpcr ) / Vims d[Cri]/dt = (-Vmick -Jpcr ) / Vims d[Pii]/dt = (-Vsyn -Jpi ) / Vims This model is hosted on BioModels Database and identified by: BIOMD0000000041 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Nicolas Le Novère

PROVIDER: BIOMD0000000041 | BioModels | 2005-06-29

REPOSITORIES: BioModels

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Regulation of mitochondrial respiration in heart cells analyzed by reaction-diffusion model of energy transfer.

Vendelin M M Kongas O O Saks V V

American journal of physiology. Cell physiology 20000401 4

The purpose of this study is to investigate theoretically which intracellular factors may be important for regulation of mitochondrial respiration in working heart cells in vivo. We have developed a model that describes quantitatively the published experimental data on dependence of the rate of oxygen consumption and metabolic state of working isolated perfused rat heart on workload over its physiological range (Williamson JR, Ford G, Illingworth J, Safer B. Circ Res 38, Suppl I, I39-I51, 1976). ...[more]

PMID: 10751324

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Project description:This model is from the article: Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling. Hettling H, van Beek JH PLoS Comput Biol.2011 Aug;7(8):e1002130. PMEDID, Abstract: In this study the function of the two isoforms of creatine kinase (CK; EC 2.7.3.2) in myocardium is investigated. The 'phosphocreatine shuttle' hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using 'sloppy modeling' ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15±8% (mean±SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 µM*s(-1)) in myofibrils. CK inhibition by 98% in silico leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215±23 to 566±31 µM*s(-1), while amplitudes of oscillations in cytosolic ADP concentration double from 77±11 to 146±1 µM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. To explain this discrepancy between the ongoing heart failure and maintained ATP levels in MuRF1 Tg+ hearts, we compared the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts. Although mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, total CK activity was significantly inhibited. We conclude that MuRF1’s inhibition of CK activity leads to increased susceptibility to heart failure following TAC, demonstrating for the first time that MuRF1 regulates cardiac energetics in vivo. Keywords: Genetic modification, physiological manipulation. Three-condition experiment, MuRF1 Tg+ vs. WT mice. Biological replicates: 4 WT baseline, 3 MuRF1 Tg+ baseline, cardiac overpressure hypertrophy induced by trans-aortic banding at 1 week (3 WT, 3 MurF Tg) and 4 weeks (3 WT, 3 MurF Tg), hearts harvested. One replicate per array.

Dataset Information

Kongas2007 - Creatine Kinase in energy metabolic signaling in muscle

Publications

Regulation of mitochondrial respiration in heart cells analyzed by reaction-diffusion model of energy transfer.

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