Critical role of cardiac t-tubule system for the maintenance of contractile function revealed by a 3D integrated model of cardiomyocytes

Abstract

T-tubules in mammalian ventricular myocytes constitute an elaborate system for coupling membrane depolarization with intracellular Ca(2+) signaling to control cardiac contraction. Deletion of t-tubules (detubulation) has been reported in heart diseases, although the complex nature of the cardiac excitation-contraction (E-C) coupling process makes it difficult to experimentally establish causal relationships between detubulation and cardiac dysfunction. Alternatively, numerical simulations incorporating the t-tubule system have been proposed to elucidate its functional role. However, the majority of models treat the subcellular spaces as lumped compartments, and are thus unable to dissect the impact of morphological changes in t-tubules. We developed a 3D finite element model of cardiomyocytes in which subcellular components including t-tubules, myofibrils, sarcoplasmic reticulum, and mitochondria were modeled and realistically arranged. Based on this framework, physiological E-C coupling was simulated by simultaneously solving the reaction-diffusion equation and the mechanical equilibrium for the mathematical models of electrophysiology and contraction distributed among these subcellular components. We then examined the effect of detubulation in this model by comparing with and without the t-tubule system. This model reproduced the Ca(2+) transients and contraction observed in experimental studies, including the response to beta-adrenergic stimulation, and provided detailed information beyond the limits of experimental approaches. In particular, the analysis of sarcomere dynamics revealed that the asynchronous contraction caused by a large detubulated region can lead to impairment of myocyte contractile efficiency. These data clearly demonstrate the importance of the t-tubule system for the maintenance of contractile function.

Distinct Functional Roles of Cardiac Mitochondrial Subpopulations Revealed by a 3D Simulation Model

“…The validity of our previous model has already been determined with regard to a number of phenomena, i.e., an averaged and local [Ca 2þ ] time course consistent with experimental observations (12), the mitochondrial response to changing contraction frequency (14), and Ca 2þ propagation with deletion of t-tubules (13). Accordingly, here we examined newly added functional components, specifically, oxygen diffusion, myoglobin buffering, and oxidative phosphorylation dependence on local oxygen concentration.…”

“…The 3D cardiomyocyte model has been previously reported and validated (12,13). Briefly, a segment containing three myofibrils of one sarcomere length, together with the adjacent cell membrane and organelles, was modeled using the FEM (Fig.…”

“…In particular, detailed three-dimensional (3D) cell models of subcellular organelles and functional molecules are a powerful tool. Using the finite-element method (FEM), we previously developed a 3D model of cardiomyocytes (12)(13)(14). In that model, detailed cardiac electrophysiology, Ca 2þ dynamics, ATP metabolism localized to specific loci, Ca 2þ and energy metabolite diffusion, and deformation by sarcomere force generation were simulated along with subcellular structures.…”

Automated generation of tissue-specific three-dimensional finite element meshes containing ellipsoidal cellular inclusions

“…FE models have been developed to explore cellular mechanics and mechanotransduction in a range of tissues, including cardiac muscle (Hatano et al 2012), intervertebral disc (Baer et al 2003;Cao et al 2009Cao et al , 2011, meniscus (Upton et al 2006) and cartilage (Guilak and Mow 2000;Kim et al 2008). In cartilage, the mechanical environment of chondrocytes has been explored over several decades, employing constitutive models of increasing complexity in multiphasic, ratedependent and anisotropic representations (Halloran et al 2012).…”

Modeling Effects of L-Type Ca2+ Current and Na+-Ca2+ Exchanger on Ca2+ Trigger Flux in Rabbit Myocytes with Realistic T-Tubule Geometries

“…These models permitted examination of the contribution of various cellular components to the evolution of the Ca 2+ transient under normal and certain pathological conditions. Furthermore, recent approaches have included approximate representations of the sub-cellular geometry to introduce spatial control of the predicted local and global Ca 2+ transients (Langer and Peskoff, 1996; Michailova et al, 2002; Izu et al, 2006; Koh et al, 2006; Lines et al, 2006; Means et al, 2006; Lu et al, 2009; Soeller et al, 2009; Cheng et al, 2010, 2011, 2012a,b; Louch et al, 2010; Hatano et al, 2011, 2012; Sato and Bers, 2011; Yu et al, 2011; Hake et al, 2012). Lu et al (2009) introduced a cylindrical representation of a t-tubule of rat ventricular myocytes.…”