Volland, Cornelia and Bremer, Sebastian and Hellenkamp, Kristian and Hartmann, Nico and Dybkova, Nataliya and Khadjeh, Sara and Kutschenko, Anna and Liebetanz, David and Wagner, Stefan and Unsoeld, Bernhard and Didie, Michael and Toischer, Karl and Sossalla, Samuel and Hasenfuss, Gerd and Seidler, Tim (2016) Enhanced cardiac TBC1D10C expression lowers heart rate and enhances exercise capacity and survival. SCIENTIFIC REPORTS, 6: 33853. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPERTROPHY; CALCINEURIN; DEATH; MICE; RAS; ASSOCIATION; CONDUCTION; MORTALITY; SEIZURES; FAILURE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Mar 2019 07:47 |
| Last Modified: | 27 Mar 2019 07:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3274 |
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