We recently identified a novel ERK-dependent pathway that is specifically activated during concentric hypertrophy (growth in width) that regulates where translation initiation occurs in adult cardiomyocytes. Nuclear ERK phosphorylates a specific serine residue in the translation repressor 4EBP1 to mediate this spatial regulation. We are now actively exploring whether this pathway could be dysregulated in diseases such as hypertrophic cardiomyopathy and working to identify the specific mRNA that are targeted for translation during early concentric hypertrophy. 

A control (left) and phenylephrine treated (right) adult rat cardiomyocytes labeled for translation initiation sites in black.

Protein synthesis machinery (mRNA, ribosomes, and nascent proteins) are highly compartmentalized at z-disks and intercalated discs in cardiomyocytes. Ongoing work in the Uchida lab seeks to understand how protein synthesis is spatially organized in the heart to drive the formation of complex structures such as the sarcomere.

The localization of translation machinery (newly synthesized proteins, ribosomes, and mRNA) to the z-disk and intercalated discs (white arrow heads) is dependent on an intact microtubule network.