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Sci Adv. 2015;1(1). pii: e1400205.

Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling.

Author information

1
Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute of Vermont, The University of Vermont, Burlington, VT 05405, USA.
2
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA ; Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam-Si 461-701, Gyeonggi-Do, Republic of Korea.
4
Department of Pediatrics and the Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
5
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
6
Department of Physiology, Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Abstract

The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by exquisitely sensitizing the contractile apparatus to calcium in a manner that precisely counterbalances the calcium gradient. Thus, the presence and correct localization of MyBP-C within the sarcomere is critically important for normal cardiac function, and any disturbance of MyBP-C localization or function will contribute to the consequent cardiac pathologies.

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