Table 1.
Cardiac effects of genetic and pharmacological mTOR modulation during development, physiology and stress.
| Cardiac condition | mTOR modulation/ animal model | Cellular modifications and cardiac outcomes | Reference |
|---|---|---|---|
| Development/physiological conditions | Constitutive cardiac mTOR gene deletion | ↑ Early mortality, heart failure, cardiac dilatation, cardiac dysfunction | 14 |
| Constitutive cardiac rictor gene deletion | ↓ Cardiac function over time | 19 | |
| Inducible cardiac mTOR gene deletion during adulthood | ↑ Apoptosis, mitochondrial dysfunction, autophagy, sarcomere disarray ↓ Protein synthesis ↑ Early mortality, heart failure, cardiac dilatation, cardiac dysfunction |
15,16 | |
| Constitutive cardiac mTOR gene deletion at early post-natal stage | ↑ Apoptosis ↓ Protein synthesis ↑ Early mortality, hypoxia, cardiac dilatation |
39 | |
| Constitutive cardiac Rheb gene deletion | ↓ Protein synthesis ↑ Early mortality, heart failure, cardiac growth, cardiac dysfunction |
17 | |
| Aging | mTOR inhibition using rapamycin | ↑ Energy metabolism ↓ Heart inflammation, cardiac fibrosis |
22 |
| Systemic GSK-3α gene deletion | ↓ Autophagy ↑ Sarcomere disarray ↑ Early mortality, cardiac hypertrophy, cardiac dysfunction during aging |
107 | |
| Cardiac hypertrophy | Inducible cardiac mTOR gene deletion during adulthood and pressure overload | ↓ Protein synthesis ↓ Compensatory hypertrophy ↑ Cardiac dysfunction, heart failure |
15,16 |
| mTOR inhibition using rapamycin and pressure overload | ↑ Cardiac function ↓ Cardiac hypertrophy |
110 | |
| mTOR inhibition using rapamycin and TAC | ↓ Cardiac hypertrophy, cardiac dysfunction | 113 | |
| mTOR inhibition using Akt inhibitor and volume overload | ↓ Eccentric hypertrophy | 114 | |
| Constitutive heterozygous cardiac Rheb gene deletion and pressure overload | ↓ Cardiac hypertrophy, cardiac fibrosis | 23 | |
| Cardiac PRAS40 overexpression and pressure overload | ↓ Cardiac hypertrophy, cardiac fibrosis ↑ Cardiac function |
115 | |
| Systemic TSC1 overexpression and isoproterenol administration | ↓ Cardiac hypertrophy ↑ Cardiac function |
116 | |
| Epigenetic mTOR inhibition and pressure overload | ↓ Cardiac hypertrophy ↑ Cardiac function |
119,120 | |
| Constitutive cardiac rictor gene deletion and pressure overload | ↑ Apoptosis ↑ Cardiac dilatation ↓ Compensatory hypertrophy |
19 | |
| Inducible cardiac rictor gene deletion during adulthood and pressure overload | ↑ Cardiac dysfunction, cardiac dilatation | 18 | |
| Ischemic injury | Cardiac Rheb overexpression during prolonged ischemia | ↓ Autophagy ↑ Apoptosis ↑ Infarct size |
59 |
| Cardiac dominant negative GSK-3β overexpression and systemic heterozygous GSK-3β deletion during prolonged ischemia | ↓ Autophagy ↑ Ischemic injury |
84 | |
| Cardiac PRAS40 overexpression during chronic myocardial infarction | ↓ Apoptosis ↓ Ischemic injury, cardiac remodeling ↑ Cardiac function |
20 | |
| mTOR inhibition using everolimus and chronic myocardial infarction | ↑ Autophagy ↓ Cardiac remodeling, infarct size, cardiac dilatation ↑ Cardiac function |
25 | |
| mTOR inhibition using rapamycin and S6K inhibitor and myocardial infarction | ↓ Apoptosis ↓ Ischemic injury |
128 | |
| Cardiac rictor gene deletion and myocardial infarction | ↑ Cardiac remodeling, cardiac dysfunction | 20 | |
| Cardiac dominant negative GSK-3β overexpression and systemic heterozygous GSK-3β deletion and I/R | ↓ Reperfusion injury | 84 | |
| Genetic disorders | mTOR inhibition using rapamycin in a model of cardiomyopathy caused by mutation in Laminin A/C gene | ↑ Autophagy ↓ Cardiac remodeling ↑ Cardiac function |
54,138 |
| mTOR inhibition using rapamycin in a mouse model of LEOPARD syndrome | ↓ Cardiac hypertrophy, myocardial disarray | 136 | |
| Metabolic disorders | mTOR inhibition using rapamycin in high-fat diet-induced obesity | ↑ Autophagy ↑ Cardiac function |
141 |
| Systemic Akt2 knockout in high-fatdiet-induced obesity | ↑ Autophagy ↑ Cardiac function |
142 | |
| mTOR inhibition using rapamycin in type II diabetic mice | ↓ Plasma glucose, triglyceride levels, oxidative stress ↑ Cardiac function |
145 | |
| Cardiac PRAS40 overexpression in diabetic mice | ↑ Metabolic function, cardiac function ↓ Cardiac hypertrophy |
146 |
Legend: Akt, protein kinase B; GSK, glycogen synthase kinase; I/R, ischemia/reperfusion; mTOR, mechanistic target of rapamycin; PRAS40, proline-rich Akt substrate 40; Rheb, Ras homolog enriched in brain; rictor, rapamycin insensitive companion of mTOR; S6K, S6 kinase; TAC, transverse aortic constriction; TSC1, tuberous sclerosis protein 1.