The Functional Role of the N2B Region Within the Elastic Sarcomeric Protein Titin
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractUtilizing a N2B knockout (KO) mouse model in which the exon that encodes the cardiac-specific N2B unique sequence (N2B-Us) spring element (exon 49) has been deleted, I investigated the mechanical role of the N2B-Us, one of the three extensible regions of cardiac titin. I was able to show that the extensibility provided by the N2B-Us limits energy loss during stretch and shortening cycles of the heart (i.e., during diastole and systole). In a range of conditions, KO mice showed significant increases in hysteresis, a measure of energy loss determined from the area between the stretch and release force-sarcomere length curves, over wild type (WT) mice. Most prominently, hysteresis increased significantly from 320±46 pJ/mm2 /sarcomere in WT tissue to 650±94 pJ/mm2 /sarcomere in KO tissue that had been preconditioned with a physiological stretch-release protocol (p < 0.005). To complement this KO model, oxidative stress was used to mechanically inactivate portions of the N2B-Us of WT titin through cysteine crosslinking. This inactivation displayed a greater increase in hysteresis response in WT compared to KO tissue, (32.3±5% vs. 12.9±2.2%, p-value < 0.05). The results of this study support the concept that the mechanical function of the N2B-Us of titin is to reduce hysteresis and increase the efficiency of the cardiac cycle.