Kongas2007 - Creatine Kinase in energy metabolic signaling in muscle

  public model
Model Identifier
BIOMD0000000041
Short description
Kongas2007 - Creatine Kinase in energy metabolic signaling in muscle

This model is described in the article:

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:

  1. d[ATP]/dt = (-Vhyd -Vmmck +Jatp) / Vcyt
  2. d[ADP]/dt = ( Vhyd +Vmmck +Jadp) / Vcyt
  3. d[PCr]/dt = ( Vmmck +Jpcr ) / Vcyt
  4. d[Cr]/dt = (-Vmmck +Jpcr ) / Vcyt
  5. d[Pi]/dt = ( Vhyd + Jpi ) / Vcyt
  6. d[ATPi]/dt = (+Vsyn -Vmick -Jatp) / Vims
  7. d[ADPi]/dt = (-Vsyn +Vmick -Jadp) / Vims
  8. d[PCri]/dt = ( Vmick -Jpcr ) / Vims
  9. d[Cri]/dt = (-Vmick -Jpcr ) / Vims
  10. d[Pii]/dt = (-Vsyn -Jpi ) / Vims

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.

Format
SBML (L2V1)
Related Publication
  • Creatine kinase in energy metabolic signaling in muscle
  • Kongas O, van Beek JHGM
  • Nature Precedings 2007 2007 , DOI: 10.1038/npre.2007.1317.1
  • Institute of Cybernetics, Tallinn Technical University, Estonia; VU University Amsterdam
  • 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 phosphoryl groups 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.
Contributors
Nicolas Le Novère

Metadata information

is
BioModels Database MODEL6622188656
BioModels Database BIOMD0000000041
isDerivedFrom
PubMed 10751324
hasTaxon
Taxonomy Oryctolagus
isVersionOf
isDescribedBy

Curation status
Curated

Tags
Name Description Size Actions

Model files

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  • Model originally submitted by : Nicolas Le Novère
  • Submitted: 13-Sep-2005 15:38:05
  • Last Modified: 10-Oct-2014 11:18:10
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 10-Oct-2014 11:18:10
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Kongas2007 - Creatine Kinase in energy metabolic signaling in muscle
  • Version: 1 public model Download this version
    • Submitted on: 13-Sep-2005 15:38:05
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Kongas2001_creatine

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Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
ATPi

ATP ; ATP
0.0 μmol
PCri

N-phosphocreatine ; Phosphocreatine
0.0 μmol
PCr

N-phosphocreatine ; Phosphocreatine
0.0 μmol
ADP

ADP ; ADP
0.0 μmol
ADPi

ADP ; ADP
0.0 μmol
Cri

creatine ; Creatine
0.0 μmol
ATP

ATP ; ATP
9700.0 μmol
Reactions
Reactions Rate Parameters
ADPi + Pi => ATPi IMS*V_1*ADPi*Pi/(Ka_1*Kb_1*(1+ADPi/Ka_1+Pi/Kb_1+ADPi*Pi/(Ka_1*Kb_1))) Ka_1=800.0; Kb_1=20.0; V_1=4600.0
PCri => PCr IMS*k1_8*PCri-CYT*k1_8*PCr k1_8=14.6
ATP + Cr => PCr + ADP CYT*(Vf_3*ATP*Cr/(Kia_3*Kb_3)-Vb_3*ADP*PCr/(Kic_3*Kd_3))/(1+Cr/Kib_3+PCr/Kid_3+ATP*(1/Kia_3+Cr/(Kia_3*Kb_3))+ADP*(1/Kic_3+Cr/(Kic_3*Kib_3)+PCr/(Kid_3*Kic_3*Kd_3/Kid_3))) Vb_3=29250.0; Kid_3=4730.0; Kb_3=15500.0; Kic_3=222.4; Vf_3=6966.0; Kia_3=900.0; Kd_3=1670.0; Kib_3=34900.0
ATPi + Cri => ADPi + PCri IMS*(Vf_2*ATPi*Cri/(Kia_2*Kb_2)-Vb_2*ADPi*PCri/(Kic_2*Kd_2))/(1+Cri/Kib_2+PCri/Kid_2+ATPi*(1/Kia_2+Cri/(Kia_2*Kb_2))+ADPi*(1/Kic_2+Cri/(Kic_2*Kib_2)+PCri/(Kid_2*Kic_2*Kd_2/Kid_2))) Kia_2=750.0; Kb_2=5200.0; Vf_2=2658.0; Vb_2=11160.0; Kic_2=204.8; Kd_2=500.0; Kid_2=1600.0; Kib_2=28800.0
ADPi => ADP IMS*k1_7*ADPi-CYT*k1_7*ADP k1_7=8.16
ATPi => ATP IMS*k1_9*ATPi-CYT*k1_9*ATP k1_9=8.16
Cri => Cr IMS*k1_6*Cri-CYT*k1_6*Cr k1_6=14.6
ATP => ADP + P CYT*v_4*ATP v_4=4600.0