Titin regulation and maintenance in the cardiac sarcomere

Abstract

The giant myofilament protein titin is indispensable for the structural integrity and function of the sarcomere, however, little is known regarding the turnover of titin within the complex macromolecular sarcomere structure in contracting cardiomyocytes. This dissertation presents novel and unique insight into the homeostatic control of titin in the cardiac sarcomere; nevertheless, the projects described in this dissertation served to elucidate key components in our understanding of the titin life cycle. The experiments described in the following chapters have addressed 3 major findings. 1) Titin is post-transcriptionally regulated at its 5’-UTR via cis-regulatory uORFs. 2) Titin is post-transcriptionally regulated by miR-26a/b at its 3’-UTR. 3) Titin is not a dynamic and mobile protein that is undergoing continuous exchange between myofibrils.