A Three-Dimensional Simulation Model of Cardiomyocyte Integrating Excitation-Contraction Coupling and Metabolism

Abstract

Recent studies have revealed that Ca2+ not only regulates the contraction of cardiomyocytes, but can also function as a signaling agent to stimulate ATP production by the mitochondria. However, the spatiotemporal resolution of current experimental techniques limits our investigative capacity to understand this phenomenon. Here, we created a detailed three-dimensional (3D) cardiomyocyte model to study the subcellular regulatory mechanisms of myocardial energetics. The 3D cardiomyocyte model was based on the finite-element method, with detailed subcellular structures reproduced, and it included all elementary processes involved in cardiomyocyte electrophysiology, contraction, and ATP metabolism localized to specific loci. The simulation results were found to be reproducible and consistent with experimental data regarding the spatiotemporal pattern of cytosolic, intrasarcoplasmic-reticulum, and mitochondrial changes in Ca2+; as well as changes in metabolite levels. Detailed analysis suggested that although the observed large cytosolic Ca2+ gradient facilitated uptake by the mitochondrial Ca2+ uniporter to produce cyclic changes in mitochondrial Ca2+ near the Z-line region, the average mitochondrial Ca2+ changes slowly. We also confirmed the importance of the creatine phosphate shuttle in cardiac energy regulation. In summary, our 3D model provides a powerful tool for the study of cardiac function by overcoming some of the spatiotemporal limitations of current experimental approaches.