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.
Highlights
Mechanistic target of rapamycin (MTOR) is a key regulator of protein synthesis in the cardiomyocyte [1, 2]
To determine whether decreased MTOR activity is associated with heart failure (HF), we studied the transverse aortic constriction (TAC) model of pressure overload
We found that 2 weeks after the TAC procedure (i.e., 3 weeks after TMX administration) Mtor-cKO mice had a significantly reduced increase in LV wall thickness and a more dilated LV chamber compared with control TAC mice (Table 2)
Summary
Mechanistic target of rapamycin (MTOR) is a key regulator of protein synthesis in the cardiomyocyte [1, 2]. Increased protein synthesis underpins hypertrophic growth, a salient feature of the heart when it is subjected to stress [3]. Regulatory associated protein of MTOR, complex 1 (Raptor); proline-rich Akt substrate 40 KDa (PRAS40); and MTOR-associated protein, LST8 homolog (Mlst8) as well as MTOR itself are the main components of MTORC1 [5]. This complex mediates temporal control of cell growth through a plethora of biological effects [6]. These include control of mRNA translation initiation via the regulation of the cap-binding eukaryotic translation initiation factor 4E (eIF-4E) through phosphorylation of eIF4E-binding proteins (4E-BPs) [7]; control of ribosome biogenesis via stimulation of polymerase I and III transcription [8]; control of mitochondrial metabolism through peroxisome proliferator-activated receptor, γ, coactivator 1 α and YY1 transcription factor [9]; and suppression of autophagy by negatively regulating the association between autophagy-related gene 1 (Atg1) and Atg13 [10]
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