In a bifluorescently labeled knockin mouse model, titin integration, disintegration, and reintegration into the sarcomere lattice are stochastic and do not proceed sequentially from Z-disk to M-band.
This study reveals that titin integration into the sarcomere is stochastic and compartmentalized differently in adult versus embryonic cardiomyocytes, providing new insights into cardiac development and remodeling.
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.
Rudolph et al. (Fri,) reported a other. Bifluorescently labeled knockin mouse model was evaluated on Titin protein synthesis, movement, insertion, detachment, and degradation. In a bifluorescently labeled knockin mouse model, titin integration, disintegration, and reintegration into the sarcomere lattice are stochastic and do not proceed sequentially from Z-disk to M-band.