Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion.
Diet-induced obesity deteriorates the recovery of cardiac function after ischemia-reperfusion (I/R) injury. While mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, the effects of cardiac mTOR in ischemic injury under metabolic syndrome remains undefined. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg mice), we studied the effect of mTOR on cardiac function in both ex vivo and in vivo models of I/R injury in high-fat diet (HFD)-induced obese mice. mTOR-Tg and wild-type (WT) mice were fed a HFD (60% fat by calories) for 12 wk. Glucose intolerance and insulin resistance induced by the HFD were comparable between WT HFD-fed and mTOR-Tg HFD-fed mice. Functional recovery after I/R in the ex vivo Langendorff perfusion model was significantly lower in HFD-fed mice than normal chow diet-fed mice. mTOR-Tg mice demonstrated better cardiac function recovery and had less of the necrotic markers creatine kinase and lactate dehydrogenase in both feeding conditions. Additionally, mTOR overexpression suppressed expression of proinflammatory cytokines, including IL-6 and TNF-α, in both feeding conditions after I/R injury. In vivo I/R models showed that at 1 wk after I/R, HFD-fed mice exhibited worse cardiac function and larger myocardial scarring along myofibers compared with normal chow diet-fed mice. In both feeding conditions, mTOR overexpression preserved cardiac function and prevented myocardial scarring. These findings suggest that cardiac mTOR overexpression is sufficient to prevent the detrimental effects of diet-induced obesity on the heart after I/R, by reducing cardiac dysfunction and myocardial scarring.
['Aoyagi|Toshinori|T|', 'Higa|Jason K|JK|', 'Aoyagi|Hiroko|H|', 'Yorichika|Naaiko|N|', 'Shimada|Briana K|BK|', 'Matsui|Takashi|T|']
D000818:Animals D059305:Diet, High-Fat D004195:Disease Models, Animal D018149:Glucose Intolerance D018836:Inflammation Mediators D007333:Insulin Resistance D008297:Male D008822:Mice, Transgenic D009200:Myocardial Contraction D009203:Myocardial Infarction D015428:Myocardial Reperfusion Injury D009206:Myocardium D009336:Necrosis D009765:Obesity D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases D013997:Time Factors D016277:Ventricular Function, Left D017725:Ventricular Pressure D020257:Ventricular Remodeling D015430:Weight Gain
diet-induced obesity metabolic syndrome transgenic mice heart failure mammalian target of rapamycin myocardial infarction