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

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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.

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Acknowledgments

This effort was supported by NIH HL grants R01 HL114904 (B.J.B.), R01 HL091986 (J.P.D.), K02 HL094692 (M.T.Z.), and R01113084 (P.M.L.J.). This article does not contain any studies with human or animal subjects performed by the any of the authors.

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Brandon J. Biesiadecki declares that he has not conflict of interest. Jonathan P. Davis declares that he has no conflict of interest. Mark T. Ziolo declares that he has no conflict of interest. Paul M.L. Janssen declares that he has no conflict of interest.

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  1. Department of Physiology and Cell Biology and Dorothy M. Davis Heart Lung Institute, College of Medicine, The Ohio State University, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210-1218, USA

    Brandon J. Biesiadecki, Jonathan P. Davis, Mark T. Ziolo & Paul M. L. Janssen

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Biesiadecki, B.J., Davis, J.P., Ziolo, M.T. et al. Tri-modal regulation of cardiac muscle relaxation; intracellular calcium decline, thin filament deactivation, and cross-bridge cycling kinetics. Biophys Rev 6, 273–289 (2014). https://doi.org/10.1007/s12551-014-0143-5

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