Dual Translational Control in Cardiomyocytes by Heterogeneous mTORC1 and Hypertrophic ERK Activation.

Background: Cardiac hypertrophy allows post-mitotic cardiomyocytes to meet increased hemodynamic demands but can predispose the heart to adverse clinical outcomes. Despite its central role in cardiac adaptation, the translational control mechanisms that drive cardiac hypertrophy are poorly understood. In this study, we elucidate the relative contributions of the various translational control mechanisms operant during homeostasis and hypertrophic growth. Methods: A combination of immunofluorescence and single myocyte protein synthesis assays were used to dissect the single-cardiomyocyte mechanisms of translational control under basal and hypertrophic conditions in isolated adult rat cardiomyocytes. Translational control mechanism were examined in a mouse model of acute hypertrophic phenylephrine (PE) stimulation prior to overt cardiac growth. Results: We observed strikingly heterogeneous activity of mTORC1, the master regulator of translation, across cardiomyocytes both Conclusions: Protein synthesis is heterogeneous across cardiomyocytes driven by heterogeneous mTORC1 activity. MEK-ERK signaling directly controls 4EBP1 phosphorylation to augment translation during cardiac hypertrophy and challenges the canonical model of translation initiation.