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) 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.
Louch
William E
WE
Institute for Experimental Medical Research, Ullevaal University Hospital, 0407 Oslo, Norway. w.e.louch@medisin.uio.no
Mørk
Halvor K
HK
Sexton
Joseph
J
Strømme
Taevje A
TA
Laake
Petter
P
Sjaastad
Ivar
I
Sejersted
Ole M
OM
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism / Q000648:ultrastructure*; D020013:Calcium Signaling; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure*; D015398:Signal Transduction / Q000502:physiology
D015220:Calcium Channels; D002118:Calcium