Microtubules Orchestrate Local Translation to Enable Cardiac Growth

Abstract

Cardiomyocytes are terminally differentiated cells that respond to stress by regulating their size. During hypertrophy, it is well established that cardiomyocytes activate a hypertrophic transcriptional profile and increase protein translation rates, yet how these changes in transcription and translation are coupled to the sarcomerogenesis remains unclear. Concomitantly, the microtubule network of cardiomyocytes proliferates and is dramatically altered by post-translational modifications and decoration by microtubule-associated proteins, but how the microtubule network may regulate hypertrophy is also unknown. Here, we demonstrate that microtubules are critical for proper localization of the translational machinery (mRNA, ribosomes, and nascent proteins) to the z-disk and intercalated discs of adult rat ventricular myocytes (aRVMs). Microtubule disruption or knockdown of the kinesin-1 motor, but not disruption of the actinomyosin network, causes perinuclear accumulation of the translational machinery in aRVMs. Map4 overexpression or tyrosination of the microtubule network by TTL overexpression or VASH knock down led to similar perinuclear mRNA accumulation. In neonatal rat ventricular myocytes treated with the hypertrophic agonist phenylephrine (PE), mRNA and nascent proteins are redistributed to the periphery during cell growth. Microtubule disruption led to perinuclear accumulation of the translational machinery similar to that observed in aRVMs and prevented the PE-induced hypertrophic growth. Importantly, this lack of hypertrophic growth was not due to a defect in upstream transcriptional or translational regulation as the expression of hypertrophic/fetal gene markers and the enhancement of translation rate was preserved with microtubule disruption, suggesting that localization of the translational machinery is the key factor driving hypertrophic growth. Furthermore, PE-induced hypertrophy in mice is abrograted by colchicine treatment despite augmented expression of hypertrophic/fetal gene markers and increased protein translation rates. Overall, the data demonstrate that microtubule-based trafficking of the translational machinery is critical to couple hypertrophic signaling pathways to productive cardiomyocyte growth.