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Basic Research in Cardiology

, 114:47 | Cite as

Glucocorticoids preserve the t-tubular system in ventricular cardiomyocytes by upregulation of autophagic flux

  • Thomas SeidelEmail author
  • Dominik J. Fiegle
  • Tim J. Baur
  • Anne Ritzer
  • Sandra Nay
  • Christian Heim
  • Michael Weyand
  • Hendrik Milting
  • Robert H. Oakley
  • John A. Cidlowski
  • Tilmann VolkEmail author
Original Contribution
  • 381 Downloads

Abstract

A major contributor to contractile dysfunction in heart failure is remodelling and loss of the cardiomyocyte transverse tubular system (t-system), but underlying mechanisms and signalling pathways remain elusive. It has been shown that dexamethasone promotes t-tubule development in stem cell-derived cardiomyocytes and that cardiomyocyte-specific glucocorticoid receptor (GR) knockout (GRKO) leads to heart failure. Here, we studied if the t-system is altered in GRKO hearts and if GR signalling is required for t-system preservation in adult cardiomyocytes. Confocal and 3D STED microscopy of myocardium from cardiomyocyte-specific GRKO mice revealed decreased t-system density and increased distances between ryanodine receptors (RyR) and L-type Ca2+ channels (LTCC). Because t-system remodelling and heart failure are intertwined, we investigated the underlying mechanisms in vitro. Ventricular cardiomyocytes from failing human and healthy adult rat hearts cultured in the absence of glucocorticoids (CTRL) showed distinctively lower t-system density than cells treated with dexamethasone (EC50 1.1 nM) or corticosterone. The GR antagonist mifepristone abrogated the effect of dexamethasone. Dexamethasone improved RyR–LTCC coupling and synchrony of intracellular Ca2+ release, but did not alter expression levels of t-system-associated proteins junctophilin-2 (JPH2), bridging integrator-1 (BIN1) or caveolin-3 (CAV3). Rather, dexamethasone upregulated LC3B and increased autophagic flux. The broad-spectrum protein kinase inhibitor staurosporine prevented dexamethasone-induced upregulation of autophagy and t-system preservation, and autophagy inhibitors bafilomycin A and chloroquine accelerated t-system loss. Conversely, induction of autophagy by rapamycin or amino acid starvation preserved the t-system. These findings suggest that GR signalling and autophagy are critically involved in t-system preservation and remodelling in the heart.

Keywords

Autophagy Transverse tubular system Glucocorticoid receptor Excitation–contraction coupling Calcium signalling Remodelling Heart failure 

Notes

Acknowledgements

We would like to thank Celine Grüninger, Lorenz McCargo, Jessica Rinke and Ralf Rinke for excellent technical support, and Philipp Tripal from the Optical Imaging Centre Erlangen (OICE) for excellent assistance with STED microscopy.

Funding

This work was supported by grants from the Interdisciplinary Centre for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg (Grant no. J65).

Compliance with ethical standards

Conflict of interest

None declared.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Cellular and Molecular PhysiologyFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  2. 2.Muscle Research Center Erlangen (MURCE), Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  3. 3.Department of Cardiac SurgeryFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  4. 4.Erich and Hanna Klessmann Institute, Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Centre NRWRuhr-University BochumBad OeynhausenGermany
  5. 5.Signal Transduction Laboratory, Department of Health and Human ServicesNational Institute of Environmental Health Sciences, National Institutes of HealthResearch Triangle ParkUSA

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