mTOR in Growth and Protection of Hypertrophying Myocardium

Abstract

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.

Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

“…mTOR stimulates hypertrophy in Acsl1 T؊/؊ hearts. The mTOR kinase activates pathways that increase cell growth (3,12). mTOR kinase activation is required for both thyroid hormone-induced and spontaneous hypertensive rat cardiac hypertrophy (14,25).…”

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat

“…Why the magnitude of load-induced mTOR signaling may differ with insulin resistance is not clear. In addition to Akt, raptor, and TSC2, the activity of mTOR is also influenced by a myriad of other molecules, including AMP-activated protein kinase (AMPK), rictor, regulated in development and DNA damage response 2, phospholipase D, and possibly others (3,10,15,25,27,32). Recent in vitro and in vivo data have suggested that AMPK may inhibit protein synthesis through its ability to suppress mTOR activation (5,6,41).…”

The functions of mTOR in ischemic diseases

“…Other studies have indicated that mTOR is involved in preconditioning and that activation of the PI3K/Akt pathway plays a significant role in I/R preconditioning (24). Rapamycin stimulates a metabolic state that protects cardiomyocytes from I/R injury (25)(26)(27), and inhibition of mT-OR promotes the myocardial protection effect of insulin at reperfusion (28). In contrast, other studies reported that the administration of rapamycin before the onset of ischemia reduces the cardioprotective effect of ischemic preconditioning, and prior activation of Akt or S6K1 are important for cell survival after I/R (28,29).…”