P126Chronic changes in cardiac load dynamically alter T-tubule morphology and local Ca2+-induced Ca2+ release in rat ventricular cardiomyocytes

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Abstract

Purpose

Transverse (t) tubules enable tight coupling between L-type Ca2+ channels and ryanodine receptors throughout the depth of cardiomyocytes, and are disrupted in several cardiac diseases. We have previously reported that mechanical unloading can influence t-tubule structure and Calcium-induced Calcium-release (CICR). In this study, we used graded mechanical overloading and mechanical unloading to comprehensively assess the effect of load on t-tubule structure and CICR.

Methods

To test this hypothesis, rat hearts were unloaded for 4 or 8 weeks using heterotopic abdominal heart-lung transplantation, or overloaded for 6 or 10 weeks using thoracic aortic constriction. Left ventricular cardiomyocytes were isolated enzymatically and studied using confocal microscopy. Results: 10 weeks (TAC10) but not 6 weeks (TAC6) of chronic mechanical overload increased cell size (Control 45,348 ± 2373μm3, n=47 vs. TAC6 weeks 48,785 ± 2237μm3, n=60 vs. TAC10 weeks 56,066 ± 3091μm3, n=42; p < 0.05) and disrupted t-tubule regularity, which was measured as the power of the dominant frequency of the Fourier transform of Di-8-ANEPPS images (Control 1.69 ± 0.1x10^7, n=44 vs. OV 10 weeks 9.45 ± 1.0x10^6, n=33; p < 0.001), despite preserved Ca2+ transients. Unloading decreased cardiomyocyte size and induced time-dependent Ca2+ transient changes. Ca2+ transient synchronicity (measured by the variance of the time-to-peak of the Ca2+ transient) was disrupted at 8 but not 4 weeks (Control 269.6 ± 17.13ms2, n=106 vs. UN 4 weeks 331.6 ± 23.67ms2, n=46 vs. UN 8 weeks 403.5 ± 35.4ms2, n=50; p < 0.01), as was the t-tubule regularity (Control 1.59 ± 0.01x10^7, n=107 vs. UN 4 weeks 1.75 ± 0.1x10^7, n=53 vs. UN 8 weeks 1.1 ± 0.0007x10^7, n=82; p < 0.01).

Conclusions

We demonstrate that changes in load can dynamically influence t-tubule structure and CICR. Deviations from normal cardiac load are initially not associated with changes at the level of Calcium cycling but chronic load variation can lead to pathological deterioration of the t-tubules which may have functional consequences. The mechanisms by which changes in load influence t-tubule structure require further studies.

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