Impact Of N-terminal Truncation Of Cardiac Troponin I On Myofilament Chemo-mechanical Transduction: Implications For The Enhanced Cardiac Function In Hemodynamic Adaptation

Abstract

The deletion of N-terminal extension of cardiac troponin I(cTnIND) by restricted proteolysis has been recently proposed to be a novel mechanism to regulate cardiac function during hemodynamic adaptation. In vivo and isolated working heart from transgenic mice overexpressing cTnIND revealed an enhanced rate of relaxation and reduced end diastolic pressure. However, the functional effect of cTnIND on myofilament properties has not been fully evaluated. Accordingly, we determined the functional effects of cTnIND on cardiac tension cost(cross-bridge cycling), maximal tension development(Fmax) and Ca2+-sensitivity(EC50) using mechanical force- and enzyme-coupled UV absorbance measurements. Wild-type(WT) or cTnIND containing recombinant troponin(cTn) complexes were exchanged for endogenous cTn in skinned rat cardiac trabeculae. cTnIND induced a significantly reduction in Fmax and Ca2+-sensitivity but increased cross-bridge cycling rate. In addition, by using steady-state fluorescence measurements, we found that the decreased myofilament Ca2+ sensitivity is due to a decrease in Ca2+ binding affinity of the regulatory site of cTnC in the thin filament. We conclude that increased cross-bridge cycling rate by cTnIND may underlie, in part, the modulation of cardiac function and hemodynamic adaptation associated with cTnIND.Summarized TableWT (N=10)cTnIND (N=8)p valueFmax (mN/mm2)42.9 ± 5.117.8 ± 1.70.0007∗Hill4.1 ± 0.75.1 ± 0.60.2587EC50 (uM)2.6 ± 0.23.7 ± 0.20.0022∗Tension Cost7.5 ± 0.611.4 ± 1.30.0140∗ View Table in HTML