Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis
Sören Brandenburg, … , Eva A. Rog-Zielinska, Stephan E. Lehnart
Sören Brandenburg, … , Eva A. Rog-Zielinska, Stephan E. Lehnart
Published June 20, 2019
Citation Information: JCI Insight. 2019;4(12):e127116. https://doi.org/10.1172/jci.insight.127116.
View: Text | PDF
Research Article Cardiology Cell biology

Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis

  • Text
  • PDF
Abstract

Atrial dysfunction is highly prevalent and associated with increased severity of heart failure. While rapid excitation-contraction coupling depends on axial junctions in atrial myocytes, the molecular basis of atrial loss of function remains unclear. We identified approximately 5-fold lower junctophilin-2 levels in atrial compared with ventricular tissue in mouse and human hearts. In atrial myocytes, this resulted in subcellular expression of large junctophilin-2 clusters at axial junctions, together with highly phosphorylated ryanodine receptor (RyR2) channels. To investigate the contribution of junctophilin-2 to atrial pathology in adult hearts, we developed a cardiomyocyte-selective junctophilin-2–knockdown model with 0 mortality. Junctophilin-2 knockdown in mice disrupted atrial RyR2 clustering and contractility without hypertrophy or interstitial fibrosis. In contrast, aortic pressure overload resulted in left atrial hypertrophy with decreased junctophilin-2 and RyR2 expression, disrupted axial junctions, and atrial fibrosis. Whereas pressure overload accrued atrial dysfunction and heart failure with 40% mortality, additional junctophilin-2 knockdown greatly exacerbated atrial dysfunction with 100% mortality. Strikingly, transgenic junctophilin-2 overexpression restored atrial contractility and survival through de novo biogenesis of polyadic junctional membrane complexes maintained after pressure overload. Our data show a central role of junctophilin-2 cluster disruption in atrial hypertrophy and identify transgenic augmentation of junctophilin-2 as a disease-mitigating rationale to improve atrial dysfunction and prevent heart failure deterioration.

Authors

Sören Brandenburg, Jan Pawlowitz, Benjamin Eikenbusch, Jonas Peper, Tobias Kohl, Gyuzel Y. Mitronova, Samuel Sossalla, Gerd Hasenfuss, Xander H.T. Wehrens, Peter Kohl, Eva A. Rog-Zielinska, Stephan E. Lehnart

×

Figure 1

Junctophilin-2 clustering at axial tubules in atrial myocytes.

Options: View larger image (or click on image) Download as PowerPoint
Junctophilin-2 clustering at axial tubules in atrial myocytes.
(A) Junct...
(A) Junctophilin-2 (JP2) and ryanodine receptor (RyR2) immunoblots of ventricular versus atrial tissue. Unexpectedly, atrial JP2 is approximately 5-fold below ventricular levels. Dot plots are representative of 3 independent experiments. (B) Confocal imaging showing heterogeneous JP2 distribution in AMs. Larger JP2 clusters (arrowheads) occur at axial tubules (ATs) labeled with caveolin-3 (Cav3). Scale bar: 10 μm. (C) Confocal 3D projection shows JP2 clusters deep inside AMs, intersecting RyR2 clusters in transversal striations. Large JP2 clusters are distributed similar to (D) highly PKA phosphorylated RyR2 clusters. Nucleus, blue (DAPI). Yellow brackets indicate magnified regions. Scale bars: 10 μm. (E) ET images of longitudinally sectioned and (F) cross-sectioned AT structures were used for 3D reconstruction of AT-SR junctions. Scale bar: 100 nm. Red, AT-SR junctions ≤15 nm in gap width and containing RyR2-like densities; green, membrane area without apparent AT-SR junctions. (G) STED superresolution imaging of JP2 and RyR2 clusters in ventricular (VM) and atrial myocytes (AM). STED images were segmented (right) for detailed cluster analysis. Scale bar: 1 μm. Both the (H) JP2 area fraction and (I) cluster density were smaller in AMs compared with VMs. In contrast, RyR2 cluster density was significantly higher in AMs. (J) Only 28% of atrial RyR2 clusters overlap with JP2 cluster signals, and (K) overlapping JP2 clusters in AMs were significantly smaller compared with VMs. n = 3 individual hearts each for 17 VM and 15 AM cells. *P < 0.05; **P < 0.01, Student’s t test.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts