© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure
aDepartment of Medicine, University of Wisconsin, Madison, WI, USA
bDepartment of Physiology, University of Wisconsin, Madison, WI, USA
cDepartment of Surgery, University of Wisconsin, Madison, WI, USA
tjk{at}medicine.wisc.edu
* Corresponding author. H6/343 Clinical Science Center, Box 3248, 600 Highland Ave., Madison, WI 53792, USA. Tel.: +1-608-263-4856; fax: +1-608-263-0405.
Objective: The T-tubule membrane network is integrally involved in excitation–contraction coupling in ventricular myocytes. Ventricular myocytes from canine hearts with tachycardia-induced dilated cardiomyopathy exhibit a decrease in accessible T-tubules to the membrane-impermeant dye, di8-ANNEPs. The present study investigated the mechanism of loss of T-tubule staining and examined for changes in the subcellular distribution of membrane proteins essential for excitation–contraction coupling. Methods: Isolated ventricular myocytes from canine hearts with and without tachycardia-induced heart failure were studied using fluorescence confocal microscopy and membrane fractionation techniques using a variety of markers specific for sarcolemmal and sarcoplasmic reticulum proteins. Results: Probes for surface glycoproteins, Na/K ATPase, Na/Ca exchanger and Cav1.2 demonstrated a prominent but heterogeneous reduction in T-tubule labeling in both intact and permeabilised failing myocytes, indicating a true depletion of T-tubules and associated membrane proteins. Membrane fractionation studies showed reductions in L-type Ca2+ channels and β-adrenergic receptors but increased levels of Na/Ca exchanger protein in both surface sarcolemma and T-tubular sarcolemma-enriched fractions; however, the membrane fraction enriched in junctional complexes of sarcolemma and junctional sarcoplasmic reticulum demonstrated no significant changes in the density of any sarcolemmal protein or sarcoplasmic reticulum protein assayed. Conclusion: Failing canine ventricular myocytes exhibit prominent depletion of T-tubules and changes in the density of a variety of proteins in both surface and T-tubular sarcolemma but with preservation of the protein composition of junctional complexes. This subcellular remodeling contributes to abnormal excitation–contraction coupling in heart failure.
KEYWORDS Ca-channel; E-c coupling; Heart failure; Remodeling; Sarcolemma
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