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Updated: May 7, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 25, 2013
MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice
Denghong Zhang1, Riccardo Contu, Michael V G Latronico
1Department of Medicine, University of California San Diego, La Jolla, California 92093-0613, USA.
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.
Insights
Ablating mTOR in mouse hearts caused fatal cardiomyopathy. Inhibiting 4E-BP1 alongside mTOR improved heart function and survival, revealing a therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Signaling
Background:
- Mechanistic target of rapamycin (MTOR) is crucial for cell growth and energy sensing.
- MTOR inhibitors are used in cancer therapy, but its role in heart function is unclear.
- Myocardial MTOR activity is altered in heart hypertrophy and failure (HF).
Purpose of the Study:
- To investigate the role of MTOR in adult mouse myocardium.
- To determine MTOR's effect on myocardial function and response to stress.
- To explore the therapeutic potential of targeting the MTOR pathway in HF.
Main Methods:
- Genetic ablation of Mtor in adult mouse hearts.
- Induction of pressure overload to mimic cardiac stress.
- Analysis of cardiac function, apoptosis, autophagy, mitochondrial structure, and protein expression (4E-BP1).
- Combined ablation of Mtor and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1).
Main Results:
- Mtor ablation in the heart led to fatal dilated cardiomyopathy with apoptosis, autophagy, and mitochondrial dysfunction.
- Mtor-ablated mice showed impaired hypertrophy and accelerated HF progression under pressure overload.
- Simultaneous ablation of Mtor and 4E-BP1 significantly improved cardiac function, reduced apoptosis, and increased survival.
Conclusions:
- The MTORC1 signaling network is vital for myocardial response to stress.
- 4E-BP1 plays a critical role in cardiomyocyte viability and HF progression.
- Inhibiting MTORC1 signaling via 4E-BP1 antagonism may be a novel therapeutic strategy for HF.
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