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Cross-bridge interaction kinetics in rat myocardium are accelerated by strong binding of myosin to the thin filament

Daniel P. Fitzsimons, Jitandrakumar R. Patel and Richard L. Moss

1. To determine the ability of strong-binding myosin cross-bridges to activate the myocardial thin filament, we examined the Ca²⁺ dependence of force and cross-bridge interaction kinetics at 15°C in the absence and presence of a strong-binding, non-force-generating derivative of myosin subfragment-1 (NEM-S1) in chemically skinned myocardium from adult rats.

2. Relative to control conditions, application of 6 M NEM-S1 significantly increased Ca²⁺-independent tension, measured at pCa 9.0, from 0.8 ± 0.3 to 3.7 ± 0.8 mN mm^-2. Furthermore, NEM-S1 potentiated submaximal Ca²⁺-activated forces and thereby increased the Ca²⁺ sensitivity of force, i.e. the [Ca²⁺] required for half-maximal activation (pCa₅₀) increased from pCa 5.85 ± 0.05 to 5.95 ± 0.04 (change in pCa₅₀ (pCa₅₀) = 0.11 ± 0.02). The augmentation of submaximal force by NEM-S1 was accompanied by a marked reduction in the steepness of the force-pCa relationship for forces less than 0.50 P_o (maximum Ca²⁺-activated force), i.e. the Hill coefficient (n₂) decreased from 4.72 ± 0.38 to 1.54 ± 0.07.

3. In the absence of NEM-S1, the rate of force redevelopment (k_tr) was found to increase from 1.11 ± 0.21 s^-1 at submaximal [Ca²⁺] (pCa 6.0) to 9.28 ± 0.41 s^-1 during maximal Ca²⁺ activation (pCa 4.5). Addition of NEM-S1 reduced the Ca²⁺ dependence of k_tr by eliciting maximal values at low levels of Ca²⁺, i.e. k_tr was 9.38 ± 0.30 s^-1 at pCa 6.6 compared to 9.23 ± 0.27 s^-1 at pCa 4.5. At intermediate levels of Ca²⁺, k_tr was less than maximal but was still greater than values obtained at the same pCa in the absence of NEM-S1.

4. NEM-S1 dramatically reduced both the extent and rate of relaxation from steady-state submaximal force following flash photolysis of the caged Ca²⁺ chelator diazo-2.

5. These data demonstrate that strongly bound myosin cross-bridges increase the level of thin filament activation in myocardium, which is manifested by an increase in the rate of cross-bridge attachment, potentiation of force at low levels of free Ca²⁺, and slowed rates of relaxation.

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