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Journal Article

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


Mitronova,  G.
Department of NanoBiophotonics, MPI for biophysical chemistry, Max Planck Society;

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Brandenburg, S., Pawlowitz, J., Eikenbusch, B., Peper, J., Kohl, T., Mitronova, G., et al. (2019). Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis. JCI Insight, 4(12): e127116. doi:10.1172/jci.insight.127116.

Cite as: https://hdl.handle.net/21.11116/0000-0003-F25A-7
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.