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

Abstract

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.

Contribution of quantitative changes in individual ionic current systems to the embryonic development of ventricular myocytes: a simulation study

“…We then classified the simulation results for the 512 combinations according to their electrical activities and also compared the simulated results in terms of contractile force. The Kyoto model adopted a 4-state contraction model [24] to simulate cardiac cell contraction; the authors of the Kyoto model also assumed that all transition steps from cross-bridge-formed states ([T*] and [TCa*]) to cross-bridge-released states ([T] and [TCa]) are ATP-dependent, because ATP binding to a myosin head disrupts the cross-bridge formation between myosin and actin [24, 25]. Although we adopted the value of half sarcomere length (hSL, μm)—computed using the model proposed by Negroni and Lascano [23]—as a quantitative parameter for cell contraction, this value is not completely quantitatively accurate because we did not consider the developmental changes in contractile proteins.…”

Holistic and dynamic metabolic alterations of traditional Chinese medicine syndrome in a toxic heat and blood stasis syndrome rat model

“…26 The creatine/creatine phosphate shuttle system plays an essential role in energy homeostasis. 27 Creatine kinase catalyzes the reaction of ADP with phosphocreatine to generate ATP, serving as fuel in the case of energy deciency. 28 The increase of citrate cycle intermediates (isocitrate, citrate and pyruvate) and glycolysis intermediates (pyruvate and glucose) in urine samples collected at 2 h and 8 h of THBSS rats as compared with normal rats demonstrates an activated energy metabolism.…”

Cardiac myocytes and local signaling in nano-domains

“…For all of these reasons, computational models that incorporate close interaction between mitochondria and the cardiac dyad, and sensing of the local dyadic Ca 2+ signal, will be necessary in order to understand properties of beat to beat regulation of cardiac energetics, and local versus more global properties of Ca 2+ signaling. The basis for modeling these processes has been established by development of compartmental models of ATP production in cardiac mitochondria (Beard, 2005; Cortassa et al, 2003) and integration of these mitochondrial models into models of the cardiac myocyte (Cortassa et al, 2006; Cortassa et al, 2009; Matsuoka et al, 2004a; Matsuoka et al, 2004b). …”