In response to an increased hemodynamic load, such as pressure or volume overload, cardiac hypertrophy ensues as an adaptive mechanism. Although hypertrophy initially maintains ventricular function, a yet undefined derailment in this process eventually leads to compromised function (decompensation) and eventually culminates in congestive heart failure (CHF). Therefore, determining the molecular signatures induced during compensatory growth is important to delineate specific mechanisms responsible for the transition into CHF. Compensatory growth involves multiple processes. At the cardiomyocyte level, one major event is increased protein turnover where enhanced protein synthesis is accompanied by increased removal of deleterious proteins. Many pathways that mediate protein turnover depend on a key molecule, mammalian target of rapamycin (mTOR). In pressure-overloaded myocardium, adrenergic receptors, growth factor receptors, and integrins are known to activate mTOR in a PI3K-dependent and/or independent manner with the involvement of specific PKC isoforms. mTOR, described as a sensor of a cell's nutrition and energy status, is uniquely positioned to activate pathways that regulate translation, cell size, and the ubiquitin-proteasome system (UPS) through rapamycin-sensitive and -insensitive signaling modules. The rapamycin-sensitive complex, known as mTOR complex 1 (mTORC1), consists of mTOR, rapamycin-sensitive adaptor protein of mTOR (Raptor) and mLST8 and promotes protein translation and cell size via molecules such as S6K1. The rapamycin-insensitive complex (mTORC2) consists of mTOR, mLST8, rapamycin-insensitive companion of mTOR (Rictor), mSin1 and Protor. mTORC2 regulates the actin cytoskeleton in addition to activating Akt (Protein kinase B) for the subsequent removal of proapoptotic factors via the UPS for cell survival. In this review, we discuss pathways and key targets of mTOR complexes that mediate growth and survival of hypertrophying cardiomyocytes and the therapeutic potential of mTOR inhibitor, rapamycin.

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The purpose of this study was to determine the mechanism by which contraction acutely accelerates the synthesis rate of the contractile protein myosin heavy chain (MHC). Laminin-adherent adult feline cardiocytes were maintained in a serum-free medium and induced to contract at 1 Hz via electrical field stimulation. Electrical stimulation of contraction accelerated rates of MHC synthesis 28%, p < 0.05 by 4 h as determined by incorporation of [ 3 H]phenylalanine into MHC. MHC mRNA expression as measured by RNase protection was unchanged after 4 h of electrical stimulation. MHC mRNA levels in messenger ribonucleoprotein complexes and translating polysomes were examined by sucrose gradient fractionation. The relative percentage of polysomebound MHC mRNA was equal at 47% in both electrically stimulated and control cardiocytes. However, electrical stimulation of contraction resulted in a reproducible shift of MHC mRNA from smaller polysomes into larger polysomes, indicating an increased rate of initiation. This shift resulted in significant increases in MHC mRNA levels in the fractions containing the larger polysomes of electrically stimulated cardiocytes as compared with nonstimulated controls. These data indicate that the rate of MHC synthesis is accelerated in contracting cardiocytes via an increase in translational efficiency.Hypertrophic growth occurs in terminally differentiated adult cardiocytes by an increase in cellular mass via a relatively coordinate increase in the proteins comprising each of the cellular components (1). This accumulation of cardiocyte proteins occurs by an increase in rates of protein synthesis relative to rates of protein degradation (2). The anabolic changes that occur during hypertrophy of the adult myocardium are generally considered to be a compensatory response to an increase in hemodynamic load (3). As demonstrated in studies employing isolated papillary muscle preparations, both the active tension and passive strain components of load have been identified as mechanical stimuli for accelerating protein synthesis rates in adult myocardium (4, 5). These findings have been extended to isolated adult cardiocytes in culture. Rates of protein synthesis were accelerated in response to electrically stimulated cardiocyte contraction (6, 7), in response to a basal load as defined by adherence of the cardiocytes to the culture dish and establishment of a resting length (8) and in response to passive stretch of cardiocytes adherent to a deformable membrane (9). Thus, the integrity of adult cardiocytes in primary culture is maintained with respect to the ability to transduce changes in mechanical load into an anabolic response such as accelerated protein synthesis rate.The specific mechanisms by which cardiocyte protein synthesis is regulated probably occur at many levels, including transcriptional, post-transcriptional, and translational processes (10). It is well established, for example, that transcriptional and post-transcriptional mechanisms regulate steady state mRNA levels and are respon...

In adult cardiocytes, eIF4E (eukaryotic initiation factor 4E) activity and protein synthesis are increased concomitantly in response to stimuli that induce hypertrophic growth. We tested the hypothesis that increases in eIF4E activity selectively improve the translational efficiency of mRNAs that have an excessive amount of secondary structure in the 5'-UTR (5'-untranslated region). The activity of eIF4E was modified in primary cultures of adult cardiocytes using adenoviral gene transfer to increase either the amount of eIF4E or the extent of endogenous eIF4E phosphorylation. Subsequently, the effects of eIF4E on translational efficiency were assayed following adenoviral-mediated expression of luciferase reporter mRNAs that were either 'stronger' (less structure in the 5'-UTR) or 'weaker' (more structure in the 5'-UTR) with respect to translational efficiency. The insertion of G+C-rich repeats into the 5'-UTR doubled the predicted amount of secondary structure and was sufficient to reduce translational efficiency of the reporter mRNA by 48+/-13%. Translational efficiency of the weaker reporter mRNA was not significantly improved by overexpression of wild-type eIF4E when compared with the stronger reporter mRNA. In contrast, overexpression of the eIF4E kinase Mnk1 [MAP (mitogen-activated protein) kinase signal-integrating kinase 1] was sufficient to increase the translational efficiency of either reporter mRNA, independent of the amount of secondary structure in their respective 5'-UTRs. The increases in translational efficiency produced by Mnk1 occurred in association with corresponding decreases in mRNA levels. These findings indicate that the positive effect of eIF4E phosphorylation on translational efficiency in adult cardiocytes is coupled with the stability of mRNA.