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.