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

Seidel T, Fiegle D, Baur TJ, Ritzer A, Nay S, Heim C, Weyand M, Milting H, Oakley RH, Cidlowski JA, Volk T (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Basic Research in Cardiology Springer Verlag (Germany)

Book Volume: 114

Article Number: 47

Journal Issue: 6

DOI: 10.1007/s00395-019-0758-6

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.

Authors with CRIS profile

Thomas Seidel Professur für Herz-Kreislaufphysiologie Dominik Fiegle Interdisziplinäres Zentrum für Klinische Forschung IZKF-Förderlinien Anne Ritzer Professur für Herz-Kreislaufphysiologie Christian Heim Department of Cardiac Surgery Michael Weyand Lehrstuhl für Herzchirurgie Tilmann Volk Professur für Herz-Kreislaufphysiologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

IZKF-J65 (P2): Regulation of the t-system and associated proteins in cardiomyocytes by glucocorticoid receptor signaling Nov. 1, 2017 - Oct. 31, 2020

Involved external institutions

National Institute of Environmental Health Sciences (NIEHS) US United States (USA) (US) Herz- und Diabeteszentrum Nordrhein-Westfalen DE Germany (DE)

How to cite

APA:

Seidel, T., Fiegle, D., Baur, T.J., Ritzer, A., Nay, S., Heim, C.,... Volk, T. (2019). Glucocorticoids preserve the t-tubular system in ventricular cardiomyocytes by upregulation of autophagic flux. Basic Research in Cardiology, 114(6). https://doi.org/10.1007/s00395-019-0758-6

MLA:

Seidel, Thomas, et al. "Glucocorticoids preserve the t-tubular system in ventricular cardiomyocytes by upregulation of autophagic flux." Basic Research in Cardiology 114.6 (2019).

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