Examination of the Effects of Heterogeneous Organization of RyR Clusters, Myofibrils and Mitochondria on Ca2+ Release Patterns in Cardiomyocytes
Autor: | Masahiko Hoshijima, Amorita Petzer, Vijay Rajagopal, Edmund J. Crampin, Cameron G. Walker, Ivo Siekmann, Mark H. Ellisman, Christian Soeller, Anthony J. R. Hickey, David J. Crossman, Gregory T. Bass |
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Přispěvatelé: | Beard, Daniel A |
Jazyk: | angličtina |
Předmět: |
Male
Bioinformatics Wistar Biology Cardiovascular Models Biological Calcium in biology Mathematical Sciences Cellular and Molecular Neuroscience QH301 Myofibrils Models Information and Computing Sciences Genetics medicine Myocyte Animals Myocytes Cardiac Computer Simulation Calcium Signaling Rats Wistar QA Molecular Biology lcsh:QH301-705.5 Ecology Evolution Behavior and Systematics Calcium signaling Myocytes Ecology Ryanodine receptor Endoplasmic reticulum Cardiac muscle Computational Biology Ryanodine Receptor Calcium Release Channel Anatomy Biological Sciences Biological Calcium sparks Mitochondria Rats medicine.anatomical_structure Heart Disease Computational Theory and Mathematics lcsh:Biology (General) Modeling and Simulation Biophysics Calcium Myofibril Cardiac Research Article |
Zdroj: | PLoS Computational Biology, Vol 11, Iss 9, p e1004417 (2015) PLoS computational biology, vol 11, iss 9 PLoS Computational Biology |
ISSN: | 1553-734X |
Popis: | Spatio-temporal dynamics of intracellular calcium, [Ca2+]i, regulate the contractile function of cardiac muscle cells. Measuring [Ca2+]i flux is central to the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease. However, current imaging techniques are limited in the spatial resolution to which changes in [Ca2+]i can be detected. Using spatial point process statistics techniques we developed a novel method to simulate the spatial distribution of RyR clusters, which act as the major mediators of contractile Ca2+ release, upon a physiologically-realistic cellular landscape composed of tightly-packed mitochondria and myofibrils. We applied this method to computationally combine confocal-scale (~ 200 nm) data of RyR clusters with 3D electron microscopy data (~ 30 nm) of myofibrils and mitochondria, both collected from adult rat left ventricular myocytes. Using this hybrid-scale spatial model, we simulated reaction-diffusion of [Ca2+]i during the rising phase of the transient (first 30 ms after initiation). At 30 ms, the average peak of the simulated [Ca2+]i transient and of the simulated fluorescence intensity signal, F/F0, reached values similar to that found in the literature ([Ca2+]i ≈1 μM; F/F0≈5.5). However, our model predicted the variation in [Ca2+]i to be between 0.3 and 12.7 μM (~3 to 100 fold from resting value of 0.1 μM) and the corresponding F/F0 signal ranging from 3 to 9.5. We demonstrate in this study that: (i) heterogeneities in the [Ca2+]i transient are due not only to heterogeneous distribution and clustering of mitochondria; (ii) but also to heterogeneous local densities of RyR clusters. Further, we show that: (iii) these structure-induced heterogeneities in [Ca2+]i can appear in line scan data. Finally, using our unique method for generating RyR cluster distributions, we demonstrate the robustness in the [Ca2+]i transient to differences in RyR cluster distributions measured between rat and human cardiomyocytes. Author Summary Calcium (Ca2+) acts as a signal for many functions in the heart cell, from its primary role in triggering contractions during the heartbeat to acting as a signal for cell growth. Cellular function is tightly coupled to its ultra-structural organization. Spatially-realistic and biophysics-based computational models can provide quantitative insights into structure-function relationships in Ca2+ signaling. We developed a novel computational model of a rat ventricular myocyte that integrates structural information from confocal and electron microscopy datasets that were independently acquired and includes: myofibrils (protein complexes that contract during the heartbeat), mitochondria (organelles that provide energy for contraction), and ryanodine receptors (RyR, ion channels that release the Ca2+ required to trigger myofibril contraction from intracellular stores). Using this model, we examined [Ca2+]i dynamics throughout the cell cross-section at a much higher resolution than previously possible. We estimated the size of structural maladaptation that would cause disease-related alterations in [Ca2+]i dynamics. Using our methods for data integration, we also tested whether reducing the density of RyRs in human cardiomyocytes (~40% relative to rat) would have a significant effect on [Ca2+]i. We found that Ca2+ release patterns between the two species are similar, suggesting Ca2+ dynamics are robust to variations in cell ultrastructure. |
Databáze: | OpenAIRE |
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