Regulation of protein translation in adaptive versus maladaptive hypertrophy. It is likely that all hypertrophic stimuli must activate mTOR and the general protein translational machinery in order to allow the full expression of the phenotype. This is mediated via the inhibition of the tuberous sclerosis gene product, tuberin (TSC2), mutations of which lead to benign hamartomas in various tissues including the heart. TSC2 can be phosphorylated and inhibited by Akt and, in some instances, via ERK-1/2 or an ERK target. The latter may be an Akt-independent mechanism of activation of mTOR that may be particularly relevant to pathologic stress–induced growth. Shown are the pathways to ribosome biogenesis as well as the regulators of the translational machinery (initiation factors [IF] and elongation factors [EF]) regulated by mTOR in the heart. As noted in the text, recent surprising findings related to this pathway have included the limited role for S6K1 and S6K2 in both adaptive and, particularly, maladaptive hypertrophy and the identification of Akt1 as a possible antihypertrophic factor in pathologic hypertrophy but a prohypertrophic factor in physiologic hypertrophy.