Protein synthesis in the heart is a dynamic process, characterized by low synthesis rates in the adult heart that can increase substantially in periods of hypertrophy; however the regulatory mechanisms involved are unclear. New research now reveals that the dynamic regulation of PABPC1 translation, via changes in its poly(A) tail length, modulates global protein synthesis during postnatal heart development and in response to hypertrophic triggers such as endurance exercise and heart disease.

Poly(A)-binding protein 1 (PABPC1) promotes mRNA translation by binding to the poly(A) tail, a sequence of 250–300 adenosine residues that contribute to mRNA stability and translational regulation. Chorghade et al. found that PABPC1 protein, but not mRNA, was absent in adult human and mouse hearts. Suppression of PABPC1 translation was mediated by shortening of its poly(A) tail, and led to reduced global protein synthesis rates. Notably, PABPC1 poly(A) tail length and translation were partially restored during hypertrophy triggered by endurance exercise or thoracic aortic constriction in mice. “These findings provide an example of poly(A) tail-based regulation in a physiological context at a time when the field is debating whether poly(A) tail length of specific transcripts matters,” explain authors Sandip Chorghade, Joseph Seimetz, and Auinash Kalsotra.

upregulation of PABPC1 induced global protein synthesis and physiological hypertrophy in adult mice

The researchers further showed that cardiomyocyte-specific upregulation of PABPC1 induced global protein synthesis and physiological hypertrophy in adult mice. “We are excited to pursue the therapeutic potential of targeting PABPC1 in promoting healthy cardiac growth and preventing disease,” comment Seimetz and Kalsotra.