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A three-dimensional simulation model of cardiomyocyte integrating excitation-contraction coupling and metabolism.

ABSTRACT: Recent studies have revealed that Ca(2+) 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 Ca(2+); as well as changes in metabolite levels. Detailed analysis suggested that although the observed large cytosolic Ca(2+) gradient facilitated uptake by the mitochondrial Ca(2+) uniporter to produce cyclic changes in mitochondrial Ca(2+) near the Z-line region, the average mitochondrial Ca(2+) 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.

SUBMITTER: Hatano A

PROVIDER: S-EPMC3297787 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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A three-dimensional simulation model of cardiomyocyte integrating excitation-contraction coupling and metabolism.

Hatano Asuka A Okada Jun-ichi J Washio Takumi T Hisada Toshiaki T Sugiura Seiryo S

Biophysical journal 20111201 11

Recent studies have revealed that Ca(2+) 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 ...[more]

PMID: 22261047

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Project description:Calcium signaling plays a pivotal role in cardiomyocytes, coupling electrical excitation to mechanical contraction of the heart. Determining locations of active calcium release sites, and how their recruitment changes in response to stimuli and in disease states is therefore of central interest in cardiac physiology. Current algorithms for detecting release sites from live cell imaging data are however not easily validated against a known "ground truth," which makes interpretation of the output of such algorithms, in particular the degree of confidence in site detection, a challenging task. Computational models are capable of integrating findings from multiple sources into a consistent, predictive framework. In cellular physiology, such models have the potential to reveal structure and function beyond the temporal and spatial resolution limitations of individual experimental measurements. Here, we create a spatially detailed computational model of calcium release in an eight sarcomere section of a ventricular cardiomyocyte, using electron tomography reconstruction of cardiac ultrastructure and confocal imaging of protein localization. This provides a high-resolution model of calcium diffusion from intracellular stores, which can be used as a platform to simulate confocal fluorescence imaging in the context of known ground truth structures from the higher resolution model. We use this capability to evaluate the performance of a recently proposed method for detecting the functional response of calcium release sites in live cells. Model permutations reveal how calcium release site density and mitochondria acting as diffusion barriers impact the detection performance of the algorithm. We demonstrate that site density has the greatest impact on detection precision and recall, in particular affecting the effective detectable depth of sites in confocal data. Our findings provide guidance on how such detection algorithms may best be applied to experimental data and give insights into limitations when using two-dimensional microscopy images to analyse three-dimensional cellular structures.

Project description:In skeletal muscle, excitation-contraction (EC) coupling requires depolarization-induced conformational rearrangements in L-type Ca(2+) channel (Ca(V)1.1) to be communicated to the type 1 ryanodine-sensitive Ca(2+) release channel (RYR1) of the sarcoplasmic reticulum (SR) via transient protein-protein interactions. Although the molecular mechanism that underlies conformational coupling between Ca(V)1.1 and RYR1 has been investigated intensely for more than 25 years, the question of whether such signaling occurs via a direct interaction between the principal, voltage-sensing ?(1S) subunit of Ca(V)1.1 and RYR1 or through an intermediary protein persists. A substantial body of evidence supports the idea that the auxiliary ?(1a) subunit of Ca(V)1.1 is a conduit for this intermolecular communication. However, a direct role for ?(1a) has been difficult to test because ?(1a) serves two other functions that are prerequisite for conformational coupling between Ca(V)1.1 and RYR1. Specifically, ?(1a) promotes efficient membrane expression of Ca(V)1.1 and facilitates the tetradic ultrastructural arrangement of Ca(V)1.1 channels within plasma membrane-SR junctions. In this paper, we demonstrate that overexpression of the RGK protein Rem, an established ? subunit-interacting protein, in adult mouse flexor digitorum brevis fibers markedly reduces voltage-induced myoplasmic Ca(2+) transients without greatly affecting Ca(V)1.1 targeting, intramembrane gating charge movement, or releasable SR Ca(2+) store content. In contrast, a ?(1a)-binding-deficient Rem triple mutant (R200A/L227A/H229A) has little effect on myoplasmic Ca(2+) release in response to membrane depolarization. Thus, Rem effectively uncouples the voltage sensors of Ca(V)1.1 from RYR1-mediated SR Ca(2+) release via its ability to interact with ?(1a). Our findings reveal Rem-expressing adult muscle as an experimental system that may prove useful in the definition of the precise role of the ?(1a) subunit in skeletal-type EC coupling.

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Dataset Information

A three-dimensional simulation model of cardiomyocyte integrating excitation-contraction coupling and metabolism.

Publications

A three-dimensional simulation model of cardiomyocyte integrating excitation-contraction coupling and metabolism.

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