MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice.
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
Denghong
D
Department of Medicine, University of California San Diego, La Jolla, California 92093-0613, USA.
Contu
Riccardo
R
Latronico
Michael V G
MV
Zhang
Jianlin
J
Zhang
Jian Ling
JL
Rizzi
Roberto
R
Catalucci
Daniele
D
Miyamoto
Shigeki
S
Huang
Katherine
K
Ceci
Marcello
M
Gu
Yusu
Y
Dalton
Nancy D
ND
Peterson
Kirk L
KL
Guan
Kun-Liang
KL
Brown
Joan Heller
JH
Chen
Ju
J
Sonenberg
Nahum
N
Condorelli
Gianluigi
G
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*
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