Revisiting Frank-Starling: regulatory light chain phosphorylation alters the rate of force redevelopment (ktr) in a length-dependent fashion

Abstract

Force and power in cardiac muscle have a known dependence on phosphorylation of the myosin-associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (k_tr), in maximally activating [Ca²⁺]. Activation was achieved by rapidly increasing the temperature (T-jump 0.5 - 20ºC) of permeabilised trabeculae over a physiological range of sarcomere lengths (1.85 - 1.94 μm). The trabeculae were subjected to shortening ramps over a range of velocities, and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC-exchange technique, which avoids changes in the phosphorylation level of other proteins. Results show that increasing RLC phosphorylation by 50 % accelerates k_tr by ∼50 %, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30 % slows k_tr by ∼50 %, relative to the k_tr obtained for in vivo phosphorylation. Clearly phosphorylation affects the magnitude of k_tr following step shortening or ramp shortening. Using a two-state model we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross-bridges. In summary RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca²⁺] so are not explained by changes in the Ca²⁺-sensitivity of acto-myosin interactions. The length-dependence of the rate of force redevelopment, and the modulation by the state of RLC phosphorylation suggest that these effects play a role in the Frank-Starling law of the heart.

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