Critical roles of junctophilin-2 in T-tubule and excitation-contraction coupling maturation during postnatal development

Biyi Chen, Ang Guo, Caimei Zhang, Rong Chen, Yanqi Zhu, Jiang Hong, William Kutschke, Kathy Zimmerman, Robert M. Weiss, Leonid Zingman, Mark E. Anderson, Xander H.T. Wehrens, Long Sheng Song

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Emerging evidence indicates a critical role for junctophilin-2 (JP2) in T-tubule integrity and assembly of cardiac dyads in adult ventricular myocytes. In the postnatal stage, one of the critical features of myocyte maturation is development of the T-tubule system, though the mechanisms remain poorly understood. In this study, we aim to determine whether JP2 is required for normal cardiac T-tubule maturation. Methods and results: Using in situ confocal imaging of intact murine hearts, we found T-tubules were absent in both left- and right-ventricular myocytes at postnatal Day 8 and did not appear until Day 10. Quantification of T-tubule structural integrity using the T-tubule power (TTpower) index revealed a progressive increase in TT power between postnatal Days 10 and 19. By postnatal Day 19, TT powerwas similar to that in adult murine cardiomyocytes, indicative of a nearly matured T-tubule network. JP2 levels increased dramatically during development, reaching levels observed in adult hearts by postnatal Day 14. Deficiency of JP2, using a mouse model in which a JP2-specific shRNA is expressed during embryonic development, severely impaired T-tubule maturation, with equivalent decreases in the left- and right-ventricular TTpower. We also detected a gradual increase in the density of transverse but not longitudinal tubules during development, and JP2 deficiency abolished the increase in the density of transverse elements. Alterations in T-tubules caused significant reduction in Ca2+ transient amplitude and marked increase in Ca2+ release dyssynchrony, Ca2+ alternans, and spontaneous Ca2+ waves, leading to contractile failure. Conclusion: Our data identify a critical role for JP2 in T-tubule and excitation-contraction coupling maturation during development.

Original languageEnglish (US)
Pages (from-to)54-62
Number of pages9
JournalCardiovascular research
Volume100
Issue number1
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Keywords

  • Calcium
  • Excitation-contraction coupling
  • Heart development
  • Junctophilin-2
  • T-tubules

ASJC Scopus subject areas

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

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