title: A kinetic model of troponin dissociation in relation to thin filament regulation in striated muscle.
abstract: The apparent rate of troponin (Tn) dissociation from myofibrils has been used as a method to study thin filament regulation in striated muscle. The rate is dependent upon calcium and strong crossbridges and supports the three-state model for thin filament regulation. The dissociation rate of Tn is extremely low so it is not intuitively clear that such a slow process would probe thin filament regulation. We have investigated this issue by developing a simple kinetic model to explain the Tn dissociation rate measured by labeled Tn exchange in the myofibrils. Tn is composed of three interacting subunits, TnC, TnI and TnT. In our model, TnI's regulatory domain switches from actin-tropomyosin to TnC followed by TnT dissociation from actin-tropomyosin. This TnI regulatory domain switching is linked to the transition of the thin filament from the blocked state to the closed state. It is calcium dependent and several orders of magnitude faster than TnT dissociation from actin-tropomyosin. By integrating the dimensionless rate equations of this model, we have computed the time course of each of the various components. In our numerical simulations, the rate constant for TnI switching from actin-tropomyosin to TnC was varied from 10 s⁻¹ to 1000 s⁻¹ to simulate the low calcium, blocked state to high calcium, closed state. The computed progress curves for labeled Tn exchange into the myofibrils and the derived intensity ratio between the non-overlap and overlap regions well explains the intensity ratio progress curves observed experimentally. These numerical simulations and experimental observations reveal that the apparent rate of Tn dissociation probes the blocked state to closed state equilibrium of the myofibrillar thin filament.
authors.affiliation: Department of Mathematical Sciences, Indiana University-Purdue University Indianapolis, 402 N. Blackford Street, Indianapolis, IN 46202, USA. asen@iupui.edu
authors.forename: Asok K
authors.initials: AK
authors.lastname: Sen
authors.forename: Darl R
authors.initials: DR
authors.lastname: Swartz
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Gawalapu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D007700:Kinetics; D008954:Models, Biological; D054792:Muscle, Striated / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism; D014336:Troponin / Q000378:metabolism*
chemical_list: D000199:Actins; D014336:Troponin; D002118:Calcium