Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion

Abstract

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.

Mammalian target of rapamycin inhibition attenuates myocardial ischaemia–reperfusion injury in hypertrophic heart

“…Taken together, the results from our present study implicate that mTOR inhibition reduces myocardial oxidative/nitrative injury during MI/R. mTOR inhibition is not only confined to modulate oxidative stress, but also related to cardioprotective molecules [16,36]. The present study has shown that mTOR inhibition by rapamycin markedly prompted the phosphorylated eNOS expression, and low concentration of NO produced by activated eNOS is well known to confer cardioprotective effects against necrosis and apoptosis during MI/R.…”

“…Apoptosis is the major contributor for programmed cell death after MI/R injury . The involvement of mTOR in regulating cardiomyocyte apoptosis has been reported by several previous studies . Nonetheless, the underlying signalling mechanisms constituting the cytoprotective effects of mTOR inhibition remain largely unknown.…”

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

“…For the insulin tolerance test, mice were fasted for 2 h, and 1 U/kg body weight of insulin was injected i.p. In both tests, blood samples were collected at baseline and at 15,30,60,90, and 120 min after injection, and plasma glucose concentrations were measured using a commercially available glucose meter (MEDISAFE FIT; Terumo Corporation, Tokyo, Japan).…”

Insulin‐like growth factors and their potential role in cardiac epigenetics

“…This signalling loop can be potentially responsible for epigenetic activity that targets survival, proliferation and/or differentiation of cardiac cells. Physical effort has been shown to increase levels of IGF-I in muscle and physiological cardiac hypertrophy, thus inducing the IGF-I/ PI3K/Akt/P70S6K signalling pathway, and thereby increasing the protein synthesis required to build muscle; all of this can be epigenetically regulated [34,60,153,154]. On the other hand, PPAR-c ligands (such as rosiglitazone) activate tuberous sclerosis complex-2 (TSC2) inhibiting mTOR signalling [152,155] intrauterine growth restriction (IUGR), where a decrease in postnatal IGF-I mRNA variants is associated with histone 3 tri-methylation of lysine 36 at the igf1 gene (H3Me3K36).…”