Article,

T-tubule disorganization and reduced synchrony of Ca$^2+$ release in murine cardiomyocytes following myocardial infarction.

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J. Physiol., 574 (Pt 2): 519--533 (July 2006)
DOI: 10.1113/jphysiol.2006.107227

Abstract

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) Ca$^2+$ release throughout the cell. We examined whether progressive changes in T-tubule organization and Ca$^2+$ 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 Ca$^2+$ transients (fluo-4 AM, 1 Hz) showed that regions of delayed Ca$^2+$ release occurred at these gaps. Three-week CHF cells exhibited an increased number of delayed release regions, and increased overall dyssynchrony of Ca$^2+$ release. A common pattern of Ca$^2+$ 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 Ca$^2+$ release which may contribute to the slowing of SR Ca$^2+$ release in this condition.

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