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Rajagopal, V, Bass, G, Walker, CG, Crossman, DJ, Petzer, A, Hickey, A, Siekmann, I, Hoshijima, M, Ellisman, MH, Crampin, EJ and Soeller, C (2015) Examination of the Effects of Heterogeneous Organization of RyR Clusters, Myofibrils and Mitochondria on Ca2+ Release Patterns in Cardiomyocytes. PLoS Computational Biology, 11 (9). ISSN 1553-734X
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Abstract
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 structureinduced 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.
| Item Type: | Article |
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| Additional Information: | Rajagopal V, Bass G, Walker CG, Crossman DJ, Petzer A, Hickey A, et al. (2015) Examination of the Effects of Heterogeneous Organization of RyR Clusters, Myofibrils and Mitochondria on Ca2+ Release Patterns in Cardiomyocytes. PLoS Comput Biol 11(9): e1004417. https://doi.org/10.1371/journal.pcbi.1004417 |
| Uncontrolled Keywords: | 06 Biological Sciences, 08 Information And Computing Sciences, 01 Mathematical Sciences |
| Subjects: | Q Science > QA Mathematics Q Science > QH Natural history > QH301 Biology |
| Divisions: | Applied Mathematics (merged with Comp Sci 10 Aug 20) |
| Publisher: | Public Library of Science (PLoS) |
| Related URLs: | |
| Date Deposited: | 21 Sep 2017 09:29 |
| Last Modified: | 04 Sep 2021 03:50 |
| DOI or ID number: | 10.1371/journal.pcbi.1004417 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/7136 |
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