MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice
Open Access
- 2 August 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (8), 2805-2816
- https://doi.org/10.1172/jci43008
Abstract
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.Keywords
This publication has 60 references indexed in Scilit:
- mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1Proceedings of the National Academy of Sciences of the United States of America, 2010
- Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and DysfunctionPublished by Elsevier BV ,2009
- The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human diseaseCell Death & Differentiation, 2009
- Akt regulates L-type Ca2+ channel activity by modulating Cavα1 protein stabilityThe Journal of cell biology, 2009
- Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological TargetsCell, 2009
- The role of autophagy in the heartCell Death & Differentiation, 2008
- The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase CThe EMBO Journal, 2008
- Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signallingThe EMBO Journal, 2008
- Cardiac Restricted Overexpression of Kinase-dead Mammalian Target of Rapamycin (mTOR) Mutant Impairs the mTOR-mediated Signaling and Cardiac FunctionPublished by Elsevier BV ,2008
- MicroRNA-133 controls cardiac hypertrophyNature Medicine, 2007