R21C Mutation in Cardiac Troponin I Imposes Differences in the Degree of Order and Kinetics of Myosin Cross-bridges of Left and Right Ventricles




Duggal, Divya
Nagwekar, Janhavi
Rich, Ryan
Raut, Sangram
Fudala, Rafal
Das, Hriday
Gryczynski, Zygmunt
Gryczynski, Ignacy
Szczesna-Cordary, Danuta
Borejdo, Julian


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The effect of the TnI R21C mutation in the human cardiac troponin I, the mutation that is linked to hypertrophic cardiomyopathy, on muscles of the left (LV) and right (RV) ventricles was examined in knock-in mice. Experiments probed 3-4 actin molecules in ex-vivo myofibrils prepared from LV and RV muscles. Control anisotropy experiments revealed that the orientation of actin reflected orientation of cross-bridges (XBs). It was found that the mutation imposed significant difference on the XB kinetics cycle of the LV and RV: XBs from RV displayed a 3-fold decrease in the rate of power stroke and a 2-fold decrease in the rate of dissociation from thin filaments as compared to LV. The mutation also imposed significant differences in the distribution of angles that actin makes with thin filament axis: during contraction, actin angles from LV were more tightly distributed compared to actin angles from RV. We speculate that molecular differences between ventricles are caused by inability of XBs to dissociate promptly from thin filaments. This work reveals phenotypic differences of the R21C mutation in the left versus right mouse ventricles even though both ventricles express the same isoform of the cardiac TnI and highlights the importance of functional differences between the two ventricles of cardiac disease.


Research Appreciation Day Award Winner - 2015 Cardiovascular Research Institute Award Presentation - 1st Place Graduate Student
Research Appreciation Day Award Winner - 2015 Graduate Student Association Awards - 2nd Place Poster