Resolving titin's lifecycle and the spatial organization of protein turnover in mouse cardiomyocytes

Item Type:	Article
Title:	Resolving titin's lifecycle and the spatial organization of protein turnover in mouse cardiomyocytes
Creators Name:	Rudolph, F. and Hüttemeister, J. and da Silva Lopes, K. and Jüttner, R. and Yu, L. and Bergmann, N. and Friedrich, D. and Preibisch, S. and Wagner, E. and Lehnart, S.E. and Gregorio, C.C. and Gotthardt, M.
Abstract:	Cardiac protein homeostasis, sarcomere assembly, and integration of titin as the sarcomeric backbone are tightly regulated to facilitate adaptation and repair. Very little is known on how the >3-MDa titin protein is synthesized, moved, inserted into sarcomeres, detached, and degraded. Here, we generated a bifluorescently labeled knockin mouse to simultaneously visualize both ends of the molecule and follow titin's life cycle in vivo. We find titin mRNA, protein synthesis and degradation compartmentalized toward the Z-disk in adult, but not embryonic cardiomyocytes. Originating at the Z-disk, titin contributes to a soluble protein pool (>15% of total titin) before it is integrated into the sarcomere lattice. Titin integration, disintegration, and reintegration are stochastic and do not proceed sequentially from Z-disk to M-band, as suggested previously. Exchange between soluble and integrated titin depends on titin protein composition and differs between individual cardiomyocytes. Thus, titin dynamics facilitate embryonic vs. adult sarcomere remodeling with implications for cardiac development and disease.
Keywords:	Sarcomere, Titin, Proteostasis, Live Imaging, STED Microscopy, Animals, Mice
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	116
Number:	50
Page Range:	25126-25136
Date:	10 December 2019
Official Publication:	https://doi.org/10.1073/pnas.1904385116
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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