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.
Users
Please
log in to take part in the discussion (add own reviews or comments).