| First Author | Gonzalez-Martinez D | Year | 2018 |
| Journal | J Mol Cell Cardiol | Volume | 123 |
| Pages | 26-37 | PubMed ID | 30138628 |
| Mgi Jnum | J:307891 | Mgi Id | MGI:6726018 |
| Doi | 10.1016/j.yjmcc.2018.08.015 | Citation | Gonzalez-Martinez D, et al. (2018) Structural and functional impact of troponin C-mediated Ca(2+) sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle. J Mol Cell Cardiol 123:26-37 |
| abstractText | Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca(2+) sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca(2+)-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca(2+) sensitizer. Our findings suggest that both methods of increasing myofilament Ca(2+) sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (kTR); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I1,1/I1,0 ratio from X-ray diffraction. Computational modeling suggests that Ca(2+) sensitization through this cTnC mutation or bepridil accelerates kTR primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in kTR, we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca(2+) activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controls force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca(2+) sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca(2+) activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM. |
