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 beta-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.

Keywords: Calcium handling; Cardiac relaxation; Contraction; Diastole; Kinetics; Myofilaments.

Fig. 1

Regulation of the rate of intracellular calcium transient decline. Left column 3 examples (no particular order) of molecular processes that fasten the rate of intracellular calcium transient decline. PLB phospholamban; NCX sodium–calcium exchanger. Right column 3 examples of molecular processes that slow down the rate of intracellular calcium transient decline

Fig. 2

Regulation of the rate of thin filament deactivation. Left column 3 examples (no particular order) of molecular processes that fasten the rate of thin filament deactivation. TnI troponin-I; TnC troponin-C; TnT troponin-T; SS slow skeletal. Right column 3 examples of molecular processes that slow down the rate of thin filament deactivation

Fig. 3

Regulation of the rate of cross-bridge cycling. Left column 3 examples (no particular order) of molecular processes that fasten the rate of cross-bridge cycling. MyBP-C myosin-binding protein C. Right column 3 examples of molecular processes that slow down the rate of cross-bridge cycling. RLC regulatory light chain

Fig. 4

Cardiac muscle relaxation is a multifaceted process. Blue squares three main processes that heavily impact on the rate of cardiac muscle relaxation. Orange ovals three main physiological processes that modulate the rate of cardiac muscle relaxation. Major direct interaction/impact between two processes is depicted by two-headed solid blue arrows, unresolved or minor interactions are depicted by two-headed gray dashed arrows. Green dashed arrows indicate the impact of a process on a rate that results in acceleration of the process. Red dashed arrows indicate the impact of a process on a rate that results in the slowing of the process. One-headed dashed gray arrows indicate unresolved, disputed, or minor impact. Red pentagons post-translational modifications can impact each regulatory component of cardiac muscle relaxation