title: MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice.
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.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093-0613, USA.
authors.forename: Denghong
authors.initials: D
authors.lastname: Zhang
authors.forename: Riccardo
authors.initials: R
authors.lastname: Contu
authors.forename: Michael V G
authors.initials: MV
authors.lastname: Latronico
authors.forename: Jianlin
authors.initials: J
authors.lastname: Zhang
authors.forename: Jian Ling
authors.initials: JL
authors.lastname: Zhang
authors.forename: Roberto
authors.initials: R
authors.lastname: Rizzi
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Katherine
authors.initials: K
authors.lastname: Huang
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceci
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000209:etiology; D002311:Cardiomyopathy, Dilated / Q000209:etiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins; D002470:Cell Survival; D039642:Eukaryotic Initiation Factors; D005260:Female; D006321:Heart / Q000502:physiology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D011506:Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases