Background and Aim
The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, protein synthesis, metabolism and autophagy. Its hyperactivation contributes to disease in different organs, including the heart. However, the role of mTORC1 and its locally regulated activity during chronic myocardial infarction (MI) remains unclear. Tuberin (TSC2) is a GTPase-activating protein and important inhibitory regulator of mTORC1. A unique knock-in (KI) mutation of TSC2 can inhibit hyperactivity of mTORC1 after pathological stimulus without losing its basal physiological function. This way, we can investigate the effects of mTORC1 in chronic MI.
Methods
We used a phospho-mimetic TSC2S1365E (TSC2SE) knock-in (KI) mouse model and wildtype controls (TSC2WT). MI was induced by surgical permanent left anterior descending artery (LAD) ligation in 8-10 weeks old mice, which were sacrificed 6 weeks later. Echocardiography was used to assess cardiac function, and western blot was used to characterize mTORC1 activity.
Results
We found that mTORC1 was activated only in the ischemic area of TSC2WT hearts. The ischemic area of TSC2SE mice had similar mTORC1 activity to sham hearts. For the remote area, both TSC2WT and TSC2SE hearts had similar activity to sham hearts. We also tested the cardiac tissue from pigs suffering LAD ligation which showed the same trend: mTORC1 was only activated in the ischemic area, not in the border zone, or remote area. Interestingly, we found TSC2S1365 was phosphorylated in the ischemic area of mouse hearts, a known inhibitory mechanism of mTORC1. After chronic LAD ligation, TSC2SE mice had higher left ventricular ejection fraction (EF) than TSC2WT mice (EF 37.4±8.0% n=20 vs. 47.6±8.2% n=21, p<0.001) suggesting that global fine-tuned inhibition of mTORC1 via genetic mimicking of TSC2S1365 phosphorylation (TSC2SE) improves cardiac function after MI.
Conclusion
Following MI, mTORC1 remained highly activated for an extended period in the ischemic area, which is associated to an impairment of the left ventricle. While TSC2SE inhibited this hyperactivation of mTORC1 in the ischemic area, it led to an improved cardiac function. The pTSC2S1365 -mTORC1 pathway is therefore a novel translational target for patients suffering from MI.
