%0 Journal Article %1 Cort_2006_1564 %A Cortassa, Sonia %A Aon, Miguel A %A O'Rourke, Brian %A Jacques, Robert %A Tseng, Hsiang-Jer %A Marb�n, Eduardo %A Winslow, Raimond L %D 2006 %J Biophys. J. %K imported %N 4 %P 1564--1589 %R 10.1529/biophysj.105.076174 %T A computational model integrating electrophysiology, contraction, and mitochondrial bioenergetics in the ventricular myocyte. %U http://dx.doi.org/10.1529/biophysj.105.076174 %V 91 %X An intricate network of reactions is involved in matching energy supply with demand in the heart. This complexity arises because energy production both modulates and is modulated by the electrophysiological and contractile activity of the cardiac myocyte. Here, we present an integrated mathematical model of the cardiac cell that links excitation-contraction coupling with mitochondrial energy generation. The dynamics of the model are described by a system of 50 ordinary differential equations. The formulation explicitly incorporates cytoplasmic ATP-consuming processes associated with force generation and ion transport, as well as the creatine kinase reaction. Changes in the electrical and contractile activity of the myocyte are coupled to mitochondrial energetics through the ATP, Ca$^2+$, and Na$^+$ concentrations in the myoplasmic and mitochondrial matrix compartments. The pseudo steady-state relationship between force and oxygen consumption at various stimulus frequencies and external Ca$^2+$ concentrations is reproduced in both model simulations and direct experiments in cardiac trabeculae under normoxic conditions, recapitulating the linearity between cardiac work and respiration in the heart. Importantly, the model can also reproduce the rapid time-dependent changes in mitochondrial NADH and Ca$^2+$ in response to abrupt changes in workload. The steady-state and dynamic responses of the model were conferred by ADP-dependent stimulation of mitochondrial oxidative phosphorylation and Ca$^2+$ -dependent regulation of Krebs cycle dehydrogenases, illustrating how the model can be used as a tool for investigating mechanisms underlying metabolic control in the heart.

@article{Cort_2006_1564, abstract = {An intricate network of reactions is involved in matching energy supply with demand in the heart. This complexity arises because energy production both modulates and is modulated by the electrophysiological and contractile activity of the cardiac myocyte. Here, we present an integrated mathematical model of the cardiac cell that links excitation-contraction coupling with mitochondrial energy generation. The dynamics of the model are described by a system of 50 ordinary differential equations. The formulation explicitly incorporates cytoplasmic ATP-consuming processes associated with force generation and ion transport, as well as the creatine kinase reaction. Changes in the electrical and contractile activity of the myocyte are coupled to mitochondrial energetics through the ATP, {C}a$^{2+}$, and {N}a$^{+}$ concentrations in the myoplasmic and mitochondrial matrix compartments. The pseudo steady-state relationship between force and oxygen consumption at various stimulus frequencies and external {C}a$^{2+}$ concentrations is reproduced in both model simulations and direct experiments in cardiac trabeculae under normoxic conditions, recapitulating the linearity between cardiac work and respiration in the heart. Importantly, the model can also reproduce the rapid time-dependent changes in mitochondrial NADH and {C}a$^{2+}$ in response to abrupt changes in workload. The steady-state and dynamic responses of the model were conferred by ADP-dependent stimulation of mitochondrial oxidative phosphorylation and {C}a$^{2+}$ -dependent regulation of Krebs cycle dehydrogenases, illustrating how the model can be used as a tool for investigating mechanisms underlying metabolic control in the heart.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Cortassa, Sonia and Aon, Miguel A and O'Rourke, Brian and Jacques, Robert and Tseng, Hsiang-Jer and Marb�n, Eduardo and Winslow, Raimond L}, biburl = {https://www.bibsonomy.org/bibtex/24ce0687ddcf9c8c1a76b873925bc94a6/hake}, description = {The whole bibliography file I use.}, doi = {10.1529/biophysj.105.076174}, file = {Cort_2006_1564.pdf:Cort_2006_1564.pdf:PDF}, interhash = {2d88604ac0ce7bf3bec54fa97dab5482}, intrahash = {4ce0687ddcf9c8c1a76b873925bc94a6}, journal = {Biophys. J.}, keywords = {imported}, month = Aug, number = 4, pages = {1564--1589}, pii = {biophysj.105.076174}, pmid = {16679365}, timestamp = {2009-06-03T11:21:09.000+0200}, title = {A computational model integrating electrophysiology, contraction, and mitochondrial bioenergetics in the ventricular myocyte.}, url = {http://dx.doi.org/10.1529/biophysj.105.076174}, volume = 91, year = 2006 }