Enhanced cardiac TBC1D10C expression lowers heart rate and enhances exercise capacity and survival.
TBC1D10C is a protein previously demonstrated to bind and inhibit Ras and Calcineurin. In cardiomyocytes, also CaMKII is inhibited and all three targeted enzymes are known to promote maladaptive cardiomyocyte hypertrophy. Here, in accordance with lack of Calcineurin inhibition in vivo, we did not observe a relevant anti-hypertrophic effect despite inhibition of Ras and CaMKII. However, cardiomyocyte-specific TBC1D10C overexpressing transgenic mice exhibited enhanced longevity. Ejection fraction and exercise capacity were enhanced in transgenic mice, but shortening of isolated cardiomyocytes was not increased. This suggests longevity resulted from enhanced cardiac performance but independent of cardiomyocyte contractile force. In further search for mechanisms, a transcriptome-wide analysis revealed expressional changes in several genes pertinent to control of heart rate (HR) including Hcn4, Scn10a, Sema3a and Cacna2d2. Indeed, telemetric holter recordings demonstrated slower atrial conduction and significantly lower HR. Pharmacological reduction of HR was previously demonstrated to enhance survival in mice. Thus, in addition to inhibition of stress signaling, TBC1D10C economizes generation of cardiac output via HR reduction, enhancing exercise capacity and survival. TBC1D10C may be a new target for HR reduction and longevity.
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Cornelia
C
Volland
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Sebastian
S
Bremer
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Kristian
K
Hellenkamp
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Nico
N
Hartmann
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Nataliya
N
Dybkova
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Sara
S
Khadjeh
Department of Clinical Neurophysiology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Anna
A
Kutschenko
Department of Clinical Neurophysiology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
David
D
Liebetanz
Department of Internal Medicine II, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
Stefan
S
Wagner
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.|Department of Internal Medicine II, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
Bernhard
B
Unsöld
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.|Institute of Pharmacology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Michael
M
Didié
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Karl
K
Toischer
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Samuel
S
Sossalla
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Gerd
G
Hasenfuß
Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
Tim
T
Seidler
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