Key result
3-D modeling predicts branched t-tubules and heterogeneous Ca2+ flux support Ca2+ wave initiation and propagation.
A 3-D computational model of rat ventricular myocytes reveals that t-tubule microanatomy and Ca2+ flux distribution significantly impact Ca2+ signaling and wave propagation.
Hypothesis-generating for t-tubule roles in myocyte Ca2+ waves; validation in human models required before clinical relevance.
The t-tubules of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca(2+)). To investigate how the t-tubule microanatomy and the distribution of membrane Ca(2+) flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca(2+) signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca(2+) signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca(2+) flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca(2+) buffers, including the Ca(2+) indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca(2+) transients was found when the Ca(2+) flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca(2+) signals are predicted. Even at modest elevation of Ca(2+), reached during Ca(2+) influx, large and steep Ca(2+) gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca(2+) flux density along the cell membrane support initiation and propagation of Ca(2+) waves in rat myocytes.
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Cheng et al. (2010) studied Ca2+ signaling in ventricular myocytes. 3-D continuum model of Ca2+ signaling was evaluated on Ca2+ transients and spatial distribution. A 3-D continuum model of Ca2+ signaling in rat ventricular myocytes predicts that branched t-tubule structure and heterogeneous Ca2+ flux density support the initiation and propagation of Ca2+ waves.
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