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Updated: Mar 14, 2026
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Enhanced cardiac TBC1D10C expression lowers heart rate and enhances exercise capacity and survival
Cornelia Volland1, Sebastian Bremer1, Kristian Hellenkamp1
1Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
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.
Insights
TBC1D10C protein overexpression in mice enhanced longevity and cardiac performance, independent of anti-hypertrophic effects. This longevity is linked to reduced heart rate and improved exercise capacity, suggesting TBC1D10C as a target for longevity research.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Gerontology
Background:
- TBC1D10C protein inhibits Ras, Calcineurin, and CaMKII, enzymes implicated in maladaptive cardiomyocyte hypertrophy.
- Previous studies suggest these enzymes promote cardiac hypertrophy, a condition associated with reduced cardiac function.
Purpose of the Study:
- To investigate the in vivo effects of TBC1D10C overexpression in cardiomyocytes.
- To explore the mechanisms underlying TBC1D10C's impact on cardiac function, hypertrophy, and longevity.
Main Methods:
- Generation of cardiomyocyte-specific TBC1D10C overexpressing transgenic mice.
- Assessment of cardiac hypertrophy, ejection fraction, and cardiomyocyte contractility.
- Transcriptome-wide analysis and telemetric holter recordings to evaluate heart rate and conduction.
- Evaluation of exercise capacity and overall longevity.
Main Results:
- TBC1D10C overexpression did not significantly inhibit hypertrophy in vivo, despite Ras and CaMKII inhibition.
- Transgenic mice exhibited enhanced longevity, improved ejection fraction, and increased exercise capacity.
- Reduced heart rate and slower atrial conduction were observed, linked to changes in genes controlling heart rate.
- Longevity appears to stem from optimized cardiac output via heart rate reduction, not altered cardiomyocyte contractility.
Conclusions:
- TBC1D10C enhances longevity and cardiac performance in mice through mechanisms independent of anti-hypertrophic effects.
- Reduced heart rate is a key factor in TBC1D10C-mediated longevity and improved exercise capacity.
- TBC1D10C represents a potential therapeutic target for reducing heart rate and promoting longevity.
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