T‐tubule disorganization and reduced synchrony of Ca2+ release in murine cardiomyocytes following myocardial infarction

In cardiac myocytes, initiation of excitation–contraction coupling is highly localized near the T‐tubule network. Myocytes with a dense T‐tubule network exhibit rapid and homogeneous sarcoplasmic reticulum (SR) Ca2+ release throughout the cell. We examined whether progressive changes in T‐tubule organization and Ca2+ release synchrony occur in a murine model of congestive heart failure (CHF). Myocardial infarction (MI) was induced by ligation of the left coronary artery, and CHF was diagnosed by echocardiography (left atrial diameter >2.0 mm). CHF mice were killed at 1 or 3 weeks following MI (1‐week CHF, 3‐week CHF) and cardiomyocytes were isolated from viable regions of the septum, excluding the MI border zone. Septal myocytes from SHAM‐operated mice served as controls. T‐tubules were visualized by confocal microscopy in cells stained with di‐8‐ANEPPS. SHAM cells exhibited a regular striated T‐tubule pattern. However, 1‐week CHF cells showed slightly disorganized T‐tubule structure, and more profound disorganization occurred in 3‐week CHF with irregular gaps between adjacent T‐tubules. Line‐scan images of Ca2+ transients (fluo‐4 AM, 1 Hz) showed that regions of delayed Ca2+ release occurred at these gaps. Three‐week CHF cells exhibited an increased number of delayed release regions, and increased overall dyssynchrony of Ca2+ release. A common pattern of Ca2+ release in 3‐week CHF was maintained between consecutive transients, and was not altered by forskolin application. Thus, progressive T‐tubule disorganization during CHF promotes dyssynchrony of SR Ca2+ release which may contribute to the slowing of SR Ca2+ release in this condition.

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