Table 1.

Main studies that investigated the role of m TOR kinase in the regulation of cardiac physiology and response to stress in vivo.

CARDIAC CONDITION	STUDY	TYPE OF MTOR MODULATION AND ANIMAL MODEL	EFFECT ON THE HEART
DEVELOPMENT/ PHYSIOLOGICAL CONDITIONS	Zhu Y et al (9)	Constitutive α-MHC-CRE-mediated mTOR gene deletion	High embryonic lethality due to cardiac failure. Massive cardiac dilation, dysfunction, heart failure and early mortality in the postnatal stage. Metabolic derangements.
	Zhang D et al (10)	Tamoxifen-induced α-MHC-CRE-mediated mTOR deletion during adulthood	Massive cardiac dilation, apoptosis, autophagy, mitochondrial abnormalities, sarcomere disarray, cardiac dysfunction, heart failure and early mortality.
	Shende P et al (11)	Tamoxifen-induced α-MHC-CRE-mediated mTOR deletion during adulthood	Massive cardiac dilation, apoptosis, autophagy, mitochondrial abnormalities, sarcomere disarray, metabolic abnormalities, cardiac dysfunction, heart failure and early mortality.
	Tamai T et al (12)	Constitutive α-MHC-CRE-mediated rheb1 gene deletion	Reduction of mTORCl activity 5 days after birth. Defect in physiological cardiac growth. Cardiac dilation, dysfunction and heart failure. Mortality within 10 days after birth.
AGING	Flynn JM et al (14)	Pharmacological mTOR inhibition using rapamycin	Reduced age-induced cardiac inflammation and fibrosis. Upregulation of energy metabolism.
	Zhou et al (77)	Systemic GSK3-alpha deletion	Cardiac hypertrophy, dysfunction and sarcomere abnormalities during aging through mTOR activation and autophagy inhibition.
CARDIAC HYPERTROPHY	Zhang D et al (10)	Tamoxifen-induced α-MHC-CRE-mediated mTOR deletion during adulthood and pressure overload	Inhibition of compensatory hypertrophy. Inhibition of protein synthesis. Rapid cardiac dilation, apoptosis, cardiac dysfunction and heart failure.
	Shende P et al (11)	Tamoxifen-induced α-MHC-CRE-mediated mTOR deletion during adulthood and pressure overload	Inhibition of compensatory hypertrophy. Inhibition of protein synthesis. Rapid cardiac dilation, cardiac dysfunction and heart failure.
	Shioi T et al (16)	mTORC1 inhibition using rapamycin and then pressure overload	Inhibition of pathological cardiac hypertrophy and preservation of cardiac function.
	McMullen JR et al (17)	mTORC1 inhibition using rapamycin in mice with established TAC-induced cardiac hypertrophy	Regression of compensated and decompensated hypertrophy. Improved cardiac function in the latter.
	Volkers M et al (18)	AAV9-mediated PRAS40 overexpression in hearts subjected to pressure overload	Prevention of TAC-induced pathological hypertrophy and myocardial fibrosis. Maintenance of cardiac function.
	Wu X wt al (19)	Constitutive α-MHC-CRE-mediated heterozygous rheb1 gene deletion and then pressure overload	Reduction of TAC-induced hypertrophy and fibrosis.
	Marin TM et al (20)	Mouse model of LEOPARD disease treated with rapamycin	Regression of hypertrophic cardiomyopathy and cardiac disarray.
	Choi et al. (21); Ramos FJ et al (22)	Mouse model of cardiomyopathy caused by Lamin A/C mutation treated with pharmacological mTORC1 inhibition	Autophagy reactivation and improved cardiac function, muscle dystrophy and increased survival.
	Song X et al (96)	α-MHC-CRE-mediated mTOR overexpression	No increase in cardiac mass. Preservation of cardiac function and reduced myocardial inflammation through inhibition of NF-κB signaling.
CARDIAC ISCHEMIA and REPERFUSION	Sciarretta S et al (23)	Pharmacological inhibition of mTORC1 during prolonged ischemia. Prolonged ischemia in mice with a-MHC-CRE-mediated Rheb overexpression	Inhibition of ischemia-induced mTORC1 downregulation and autophagy activation. Increased infarct size after ischemia that is reversed by rapamycin treatment.
	Zhai P et al (24)	Mice with α-MHE-CRE-mediated dominant negative-GSK-3P overexpression and systemic heterozygous GSK-3ϐ deletion subjected to prolonged ischemia and I/R	GSK-3β is activated during prolonged ischemia but inhibited during reperfusion. Genetic inhibition of GSK-3β increases ischemic injury after prolonged ischemia but reduces reperfusion injury through a deregulated activation of mTORC1.
	Buss SJ et al (25)	mTORC1 inhibition with everolimus during chronic myocardial infarction	Reduction of infarct size, pathological growth and cardiac dilation. Improvement of cardiac function. Activation of autophagy.
	Volkers M et al (26)	AAV9-mediated PRAS40 cardiac overexpression and Rictor knockdown in mice subjected to chronic myocardial infarction	Overexpression of PRAS40 inhibits mTORC1, reduces ischemic injury, apoptosis and cardiac remodeling and improves cardiac function in an mT0RC2-dependent manner. Rictor knockdown causes deterioration of cardiac function and remodeling after myocardial infarction.
	Di R et al (109)	Rapamycin and S6K inhibitors during chronic myocardial infarction	Reduction of cardiac ischemic remodeling and cardiomyocte apoptosis.
	Aoyagi T et al (117)	α-MHC-CRE-mediated mTOR overexpression and I/R	Inhibition of cardiac remodeling after I/R in vivo, and reduction of necrosis and myocardial inflammation after I/R ex vivo.
METABOLIC DISORDERS	Wang CY et al (122)	Rapamycin treatment during high fat diet-induced obesity	Akt and mTOR are activated in the vasculature of obese animals. Rapamycin inhibits endothelial senescence and the increased susceptibility to peripheral ischemia in obese animals.
	Sciarretta et al (23)	Rapamycin treatment and partial inducible mTOR genetic disruption in mice with high fat diet-induced obesity and metabolic syndrome subjected to prolonged ischemia	Ischemia-induced autophagy activation is inhibited in the hearts of obese animals through deregulated activation of Rheb and mTORC1. Infarct size after ischemia is larger in obese animals. Pharmacological and partial genetic inhibition of mTOR rescue autophagy and reduce ischemic injury in obese mice.
	Li ZL et al (123)	Swine model of metabolic syndrome	Increased cardiac mTOR level and reduction of cardiac autophagy that is proportional to the degree of the derangements of cardiac structure and function.
	Guo R et al (124)	Rapamycin in mice with high fat diet-induced obesity	Increased mTOR activity and reduced autophagosome formation in the hearts of obese mice, associated with reduction of cardiac function. Cardiac function is rescued by rapamycin and deteriorated by genetic adiponectin disruption.
	Xu X et al (125)	Mice with systemic Akt2 knockout subjected to high fat diet	mTOR activation and disruption of autophagic flux in the hearts of obese mice. Akt2 deletion rescues autophagic flux and cardiac dysfunction in obese animals.
	Xu X et al (126)	Streptozotocin-induced diabetes	Cardiac autophagosome formation and flux are impaired in diabetic mice. These effects are associated with increased mTOR activity.