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Enhanced cardiac TBC1D10C expression lowers heart rate and enhances exercise capacity and survival

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Longevity and exercise endurance in TBC1D10C TG mice.(a) Kaplan–Meier analysis of survival was determined in a prospectively defined cohort of mice. Spontaneous deaths were recorded (WT: n = 79; TG: n = 86; P < 0.05; log-rank (Mantel–Cox) test). (b) Voluntary running was recorded over 5 weeks. TG mice exhibited significantly longer daily running duration at weeks 1, 3 and 4, longer running distance at weeks 1, 3, 4 and 5, and Vmax was significantly increased at weeks 1, 2 and 3 (WT: n = 6; TG: n = 8; P < 0.05). (c) Exercise-induced hypertrophy of the anterior wall (anterior wall thickness in diastole (AWthd)) was similar between WT and TG mice. Left ventricular enddiastolic diameter (LVIDD) remained unchanged.
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f5: Longevity and exercise endurance in TBC1D10C TG mice.(a) Kaplan–Meier analysis of survival was determined in a prospectively defined cohort of mice. Spontaneous deaths were recorded (WT: n = 79; TG: n = 86; P < 0.05; log-rank (Mantel–Cox) test). (b) Voluntary running was recorded over 5 weeks. TG mice exhibited significantly longer daily running duration at weeks 1, 3 and 4, longer running distance at weeks 1, 3, 4 and 5, and Vmax was significantly increased at weeks 1, 2 and 3 (WT: n = 6; TG: n = 8; P < 0.05). (c) Exercise-induced hypertrophy of the anterior wall (anterior wall thickness in diastole (AWthd)) was similar between WT and TG mice. Left ventricular enddiastolic diameter (LVIDD) remained unchanged.

Mentions: Selective targeting of heart rate by the If channel inhibitor ivabradine was recently demonstrated to enhance longevity in healthy mice. Here, we constantly observed reduced HR that was repeatedly determined until at least 12 months of age (Supplemental Fig. 4e). Therefore we hypothesized that survival might be enhanced in TG mice. Kaplan–Meier analysis of survival was conducted in a prospectively defined cohort of mice. All-cause mortality, including spontaneous death and euthanasia of mice because of sickness, was recorded (Fig. 5a). Indeed, median survival of the TG mice was significantly increased by 14 weeks compared to WT (WT: 91 weeks vs. TG: 105 weeks, P < 0.05). As survival was greater at a relatively young age, we asked whether higher exercise capacity in TBC1D10C TG mice might explain such robust difference. To address this issue, a separate cohort of mice were housed individually in cages equipped with a running wheel and we recorded voluntary running over 5 weeks. Remarkably, these examinations revealed a significantly longer running distance and duration of TBC1D10C TG compared to WT mice (Fig. 5b). Exercise-induced hypertrophy was not different between the genotypes (Fig. 5c).


Enhanced cardiac TBC1D10C expression lowers heart rate and enhances exercise capacity and survival
Longevity and exercise endurance in TBC1D10C TG mice.(a) Kaplan–Meier analysis of survival was determined in a prospectively defined cohort of mice. Spontaneous deaths were recorded (WT: n = 79; TG: n = 86; P < 0.05; log-rank (Mantel–Cox) test). (b) Voluntary running was recorded over 5 weeks. TG mice exhibited significantly longer daily running duration at weeks 1, 3 and 4, longer running distance at weeks 1, 3, 4 and 5, and Vmax was significantly increased at weeks 1, 2 and 3 (WT: n = 6; TG: n = 8; P < 0.05). (c) Exercise-induced hypertrophy of the anterior wall (anterior wall thickness in diastole (AWthd)) was similar between WT and TG mice. Left ventricular enddiastolic diameter (LVIDD) remained unchanged.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036039&req=5

f5: Longevity and exercise endurance in TBC1D10C TG mice.(a) Kaplan–Meier analysis of survival was determined in a prospectively defined cohort of mice. Spontaneous deaths were recorded (WT: n = 79; TG: n = 86; P < 0.05; log-rank (Mantel–Cox) test). (b) Voluntary running was recorded over 5 weeks. TG mice exhibited significantly longer daily running duration at weeks 1, 3 and 4, longer running distance at weeks 1, 3, 4 and 5, and Vmax was significantly increased at weeks 1, 2 and 3 (WT: n = 6; TG: n = 8; P < 0.05). (c) Exercise-induced hypertrophy of the anterior wall (anterior wall thickness in diastole (AWthd)) was similar between WT and TG mice. Left ventricular enddiastolic diameter (LVIDD) remained unchanged.
Mentions: Selective targeting of heart rate by the If channel inhibitor ivabradine was recently demonstrated to enhance longevity in healthy mice. Here, we constantly observed reduced HR that was repeatedly determined until at least 12 months of age (Supplemental Fig. 4e). Therefore we hypothesized that survival might be enhanced in TG mice. Kaplan–Meier analysis of survival was conducted in a prospectively defined cohort of mice. All-cause mortality, including spontaneous death and euthanasia of mice because of sickness, was recorded (Fig. 5a). Indeed, median survival of the TG mice was significantly increased by 14 weeks compared to WT (WT: 91 weeks vs. TG: 105 weeks, P < 0.05). As survival was greater at a relatively young age, we asked whether higher exercise capacity in TBC1D10C TG mice might explain such robust difference. To address this issue, a separate cohort of mice were housed individually in cages equipped with a running wheel and we recorded voluntary running over 5 weeks. Remarkably, these examinations revealed a significantly longer running distance and duration of TBC1D10C TG compared to WT mice (Fig. 5b). Exercise-induced hypertrophy was not different between the genotypes (Fig. 5c).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus