Ablation of Mtor in adult mouse myocardium resulted in fatal dilated cardiomyopathy, which was markedly improved by co-ablation of 4E-BP1.
Does ablation of Mtor and 4E-BP1 affect cardiac function and myocyte survival in adult mice?
MTORC1 regulates cardiomyocyte viability and heart failure progression through 4E-BP1 inhibition, identifying a potential novel therapeutic target for heart failure.
Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully elucidated. Here, we show that ablation of Mtor in the adult mouse myocardium results in a fatal, dilated cardiomyopathy that is characterized by apoptosis, autophagy, altered mitochondrial structure, and accumulation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). 4E-BP1 is an MTOR-containing multiprotein complex-1 (MTORC1) substrate that inhibits translation initiation. When subjected to pressure overload, Mtor-ablated mice demonstrated an impaired hypertrophic response and accelerated HF progression. When the gene encoding 4E-BP1 was ablated together with Mtor, marked improvements were observed in apoptosis, heart function, and survival. Our results demonstrate a role for the MTORC1 signaling network in the myocardial response to stress. In particular, they highlight the role of 4E-BP1 in regulating cardiomyocyte viability and in HF. Because the effects of reduced MTOR activity were mediated through increased 4E-BP1 inhibitory activity, blunting this mechanism may represent a novel therapeutic strategy for improving cardiac function in clinical HF.
Zhang et al. (Mon,) conducted a other in Dilated cardiomyopathy and heart failure. Mtor ablation and 4E-BP1 co-ablation was evaluated on Cardiac function, apoptosis, and survival. Ablation of Mtor in adult mouse myocardium resulted in fatal dilated cardiomyopathy, which was markedly improved by co-ablation of 4E-BP1.