1. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice
- Author
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Denghong, Zhang, Riccardo, Contu, Michael V G, Latronico, Jianlin, Zhang, Jian Ling, Zhang, Roberto, Rizzi, Daniele, Catalucci, Shigeki, Miyamoto, Katherine, Huang, Marcello, Ceci, Yusu, Gu, Nancy D, Dalton, Kirk L, Peterson, Kun-Liang, Guan, Joan Heller, Brown, Ju, Chen, Nahum, Sonenberg, and Gianluigi, Condorelli
- Subjects
Cardiomyopathy, Dilated ,Male ,Cardiac function curve ,medicine.medical_specialty ,Cell Survival ,Apoptosis ,Cardiomegaly ,Cell Cycle Proteins ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Mice ,Clinical investigation ,Internal medicine ,Eukaryotic initiation factor ,Animals ,Myocyte ,Medicine ,Initiation factor ,Myocytes, Cardiac ,Eukaryotic Initiation Factors ,Phosphorylation ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Pressure overload ,biology ,business.industry ,Cell growth ,Myocardium ,TOR Serine-Threonine Kinases ,Autophagy ,Proteins ,Heart ,General Medicine ,Phosphoproteins ,Cell biology ,Mice, Inbred C57BL ,Endocrinology ,Multiprotein Complexes ,Cardiology ,biology.protein ,Female ,Carrier Proteins ,Corrigendum ,business ,Transcription Factors ,Research Article - 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.
- Published
- 2010