Tri-modal regulation of cardiac muscle relaxation; intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics

Abstract

Cardiac muscle relaxation is an essential step in the cardiac cycle. Even when the contraction of the heart is normal and forceful, a relaxation phase that is too slow will limit proper filling of the ventricles. Relaxation is too often thought of as a mere passive process that follows contraction. However, many decades of advancements in our understanding of cardiac muscle relaxation have shown it is a highly complex and well-regulated process. In this review, we will discuss three distinct events that can limit the rate of cardiac muscle relaxation: the rate of intracellular calcium decline, the rate of thin-filament de-activation, and the rate of cross-bridge cycling. Each of these processes are directly impacted by a plethora of molecular events. In addition, these three processes interact with each other, further complicating our understanding of relaxation. Each of these processes is continuously modulated by the need to couple bodily oxygen demand to cardiac output by the major cardiac physiological regulators. Length-dependent activation, frequency-dependent activation, and β-adrenergic regulation all directly and indirectly modulate calcium decline, thin-filament deactivation, and cross-bridge kinetics. We hope to convey our conclusion that cardiac muscle relaxation is a process of intricate checks and balances, and should not be thought of as a single rate-limiting step that is regulated at a single protein level. Cardiac muscle relaxation is a system level property that requires fundamental integration of three governing systems: intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics.

In Vivo Genome Editing Restores Dystrophin Expression and Cardiac Function in Dystrophic Mice

“…Three main mechanisms of cardiac contractile regulation were assessed as previously described 22, 23 , including length dependent activation, frequency-dependent activation, and beta-adrenergic stimulation. The length-dependent activation was evaluated by recording the contractile parameters at 85, 90, 95, and 100% of optimal muscle length.…”

Decrease in sarcoplasmic reticulum calcium content, not myofilament function, contributes to muscle twitch force decline in isolated cardiac trabeculae

“…post-rest potentiation is dependent upon the SR calcium load and the amount of calcium released upon resumption of stimulation(Bers 2001). Since both force-frequency relationship and post-rest potentiation are highly dependent on calcium handling processes, changes in both of these parameters suggest alterations in the cardiomyocyte’s calcium handling mechanisms(Biesiadecki et al 2014). We should point out that the enhanced force-frequency relationship and post-rest potentiation after prolonged incubation periods have been previously reported by another group of investigators(Taylor et al 2004), although the interpretation of the data between this study and ours is different.…”

What global diastolic function is, what it is not, and how to measure it

“…Relaxation is the decay of systolic force that was generated by cross bridges (4,14). There are three prominent factors in this decline in force: calcium reuptake, deactivation of cross-bridge binding sites, and detachment of cross bridges themselves.…”

“…Altered deactivation of cross-bridge binding sites, for example due to phosphorylation or mutation of troponin complexes, is also associated with slow relaxation (73,81,118). In addition, cross-bridge detachment itself may modify the rate of relaxation (4,42), with slowed cross-bridge detachment, for example by mutation, leading to prolonged generation of force.…”

“…For example, IVR is generally referred to as a cross-bridge relaxation process (4,14,42). In general, if some cross-bridge modifying property (calcium reuptake, binding site deactivation, or cross-bridge detachment) is slowed or disrupted, relaxation is slowed, and indexes of IVR are prolonged.…”