Myofilament Calcium Sensitivity: Role in Regulation of In vivo Cardiac Contraction and Relaxation

Abstract

Myofilament calcium sensitivity is an often-used indicator of cardiac muscle function, often assessed in disease states such as hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). While assessment of calcium sensitivity provides important insights into the mechanical force-generating capability of a muscle at steady-state, the dynamic behavior of the muscle cannot be sufficiently assessed with a force-pCa curve alone. The equilibrium dissociation constant (K_d) of the force-pCa curve depends on the ratio of the apparent calcium association rate constant (k_on) and apparent calcium dissociation rate constant (k_off) of calcium on TnC and as a stand-alone parameter cannot provide an accurate description of the dynamic contraction and relaxation behavior without the additional quantification of k_on or k_off, or actually measuring dynamic twitch kinetic parameters in an intact muscle. In this review, we examine the effect of length, frequency, and beta-adrenergic stimulation on myofilament calcium sensitivity and dynamic contraction in the myocardium, the effect of membrane permeabilization/mechanical- or chemical skinning on calcium sensitivity, and the dynamic consequences of various myofilament protein mutations with potential implications in contractile and relaxation behavior.

Keywords: desensitize; kinetics; muscle; sensitize; twitch.

Figure 1

A hypothetical force-pCa curve demonstrating left- and right-shift (increased and decreased calcium sensitivity, respectively). Bottom. A biochemical equation showing calcium association rate to TnC (k_on) and calcium dissociation rate from TnC (k_off). A simple equation showing the relationship between equilibrium dissociation constant (K_d), k_on, and k_off.

Figure 2

A set of hypothetical twitches generated using a Labview (National Instruments) program demonstrating the possible effects of altered calcium sensitivity on twitch kinetics. If the decrease in calcium sensitivity (increase in K_d) is primarily due to decreased k_on, one would observe lower developed force (pink). If the decrease in calcium sensitivity is primarily due to increased k_off, one would observe lower developed force and faster relaxation kinetics (gray). If the increase in calcium sensitivity (decrease in K_d) is primarily due to decreased k_off, one would observe increased developed force and slower relaxation kinetics (dark blue). If the increase in calcium sensitivity (increase in K_d) is primarily due to increased k_on, one would observe increased developed force and faster relaxation compared to the case where k_off is decreased (green). Calcium transient (light blue) and original twitch (red) are also included in the figure.

Figure 3

A set of hypothetical twitches generated using a Labview (National Instruments) program with the same K_d demonstrating the effect of modulating k_on and k_off. When k_on and k_off are both increased by the same factor to yield the same K_d, the contraction and relaxation kinetics speed up (dark blue) and begins to more closely resemble the kinetics of the calcium transient (light blue). When k_on and k_off are both decreased by the same factor to yield the same K_d, the muscle cannot relax completely at steady-state and has a lower developed force (gray). The original twitch (red) has the same K_d as the other two tracings (dark blue and gray).