Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure

Ravi C. Balijepalli, Andrew J. Lokuta, Nathan A. Maertz, Jennifer M. Buck, Robert A. Haworth, Hector H. Valdivia, Timothy J. Kamp

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)67-77
Number of pages11
JournalCardiovascular research
Volume59
Issue number1
DOIs
StatePublished - Jul 1 2003
Externally publishedYes

Keywords

  • Ca-channel
  • E-c coupling
  • Heart failure
  • Remodeling
  • Sarcolemma

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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