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MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice
Denghong Zhang, … , Nahum Sonenberg, Gianluigi Condorelli
Denghong Zhang, … , Nahum Sonenberg, Gianluigi Condorelli
Published July 19, 2010
Citation Information: J Clin Invest. 2010;120(8):2805-2816. https://doi.org/10.1172/JCI43008.
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Research Article Cardiology

MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice

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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

Denghong Zhang, Riccardo Contu, Michael V.G. Latronico, Jianlin 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, Gianluigi Condorelli

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Figure 1

Characterization of Mtor-cKO mice.

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Characterization of Mtor-cKO mice.
   
(A) Kaplan-Meier survival curves ...
(A) Kaplan-Meier survival curves of Mtor-cKO and control (CTL) mice. Mortality of Mtor-cKO mice begins 4 weeks after TMX administration and reaches 100% by 8 weeks. Time is shown as weeks after TMX administration (n = 11 for Mtor-cKO mice; n = 7 for TMX-injected Mtorfl/fl mice [F/F] control; n = 6 for WT-Cre control). (B) Representative explanted hearts. The Mtor-cKO heart is larger than that of controls. (C) Representative H&E-stained heart sections. Mtor-cKO hearts have thinned ventricular walls and enlarged cardiac chambers. (D) Dobutamine stress test, at 4 weeks after TMX administration, of Mtor-cKO (KO) and WT-Cre control hearts. Mtor-cKO hearts have greatly hampered basal inotropy and lusitropy and have only a very weak reactivity to stimulation with increasing units of dobutamine (Dob) (mean ± SD; n = 7 per group). (E) Incorporation of [3H]leucine in cultured adult cardiomyocytes (mean ± SD; n = 3). (F) Fluorescence micrographs of heart tissue were analyzed to obtain cross-sectional cell area (mean ± SD). Cardiomyocytes become significantly and progressively smaller after the administration of TMX. (G) Expression of cardiac fetal genes (Nppa, encoding atrial natriuretic factor; Myh7, encoding β-myosin heavy chain; Acta1, encoding α1-skeletal actin), assayed by qRT-PCR and normalized for Gapdh expression, is given as fold change. Mtor-cKO hearts have a 2- to 8-fold increase in the expression of these genes with respect to controls at 2 weeks and 4 weeks after TMX administration, respectively (mean ± SD, n = 3–4 per group).

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