Institute Seminar - How the myocyte got its stripes- maintenance and growth of the cardiac sarcomere

Abstract

Cardiomyocyte can live for years, however, the turnover of sarcomeric proteins is fast and different sarcomeric proteins half-lives range between 3 and 10 days in the rat and mouse heart. Because the entire sarcomere proteome of a heart is exchanged every 2-3 weeks, continuous protein replenishment is essential. It is far from understood how the sarcomere is continuously replenished with new proteins in the normal adult heart and why this maintenance appears to ultimately fail to meet the needs of the heart, contributing to the sarcomeric dysfunction and the development of heart failure. Studies from my lab in recent years established a new paradigm for the turnover of sarcomeric proteins. We showed that mRNA and ribosomes are transported on microtubules and are localized near sarcomeres Z-lines. The sarcomeric proteins are locally produced at these facilities in access and replace the existing proteins that are stochastically cleaved and degraded. I will present published and unpublished data on our use of proximity labeling proteomics to unravel the proteome of the Z-line associated translated nanodomains and the identification of novel proteins involved in localized translation. To understand their function, we use new CRISPR-based approaches to identify, modify, or delete these proteins. We combine these with live imaging approaches to image translation and the replacement of sarcomeric proteins to understand the principles behind the turnover of the cardiomyocyte proteome.