title: Critical roles of junctophilin-2 in T-tubule and excitation-contraction coupling maturation during postnatal development.
abstract: OBJECTIVE
  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.
  
  
  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 (TT(power)) index revealed a progressive increase in TT(power) between postnatal Days 10 and 19. By postnatal Day 19, TT(power) was 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 TT(power). 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 Ca(2+) transient amplitude and marked increase in Ca(2+) release dyssynchrony, Ca(2+) alternans, and spontaneous Ca(2+) waves, leading to contractile failure.
  
  
  CONCLUSIONS
  Our data identify a critical role for JP2 in T-tubule and excitation-contraction coupling maturation during development.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver, College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.forename: Ang
authors.initials: A
authors.lastname: Guo
authors.forename: Caimei
authors.initials: C
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jiang
authors.initials: J
authors.lastname: Hong
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Kathy
authors.initials: K
authors.lastname: Zimmerman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Leonid
authors.initials: L
authors.lastname: Zingman
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000502:physiology*; D006321:Heart / Q000254:growth & development*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology*; D012508:Sarcolemma / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C412507:junctophilin; D002118:Calcium
keywords: Calcium; Excitation–contraction coupling; Heart development; Junctophilin-2; T-tubules