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

Previs MJ, Prosser BL, Mun JY, Previs SB, Gulick J, Lee K, Robbins J, Craig R, Lederer WJ, Warshaw DM - Sci Adv (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute of Vermont, The University of Vermont, Burlington, VT 05405, 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.

No MeSH data available.


Related in: MedlinePlus

Sarcomeric organization and MyBP-C(A) Cardiac muscle sarcomere with interdigitating thick and thin filaments. MyBP-C localized to the C-zone, whereas the ryanodine receptors are localized in puncta (CRUs) along the Z-lines, forming the boundaries of each sarcomere. (B) Schematic diagram of cardiac MyBP-C’s Ig-like (oval) and fibronectin-like (rectangular) domains with four phosphorylation sites (P) in the M-domain and C0C3 fragment (dashed box) used in the 3D EM and in vitro motility experiments. (C) Negatively stained EM image of a sarcomere within a mouse ventricular myocyte labeled with antibodies to MyBP-C. (D) Two-color dSTORM super-resolution image of sarcomeres as in (C), labeled with Alexa Fluor–conjugated antibodies to MyBP-C and ryanodine receptors.
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Figure 1: Sarcomeric organization and MyBP-C(A) Cardiac muscle sarcomere with interdigitating thick and thin filaments. MyBP-C localized to the C-zone, whereas the ryanodine receptors are localized in puncta (CRUs) along the Z-lines, forming the boundaries of each sarcomere. (B) Schematic diagram of cardiac MyBP-C’s Ig-like (oval) and fibronectin-like (rectangular) domains with four phosphorylation sites (P) in the M-domain and C0C3 fragment (dashed box) used in the 3D EM and in vitro motility experiments. (C) Negatively stained EM image of a sarcomere within a mouse ventricular myocyte labeled with antibodies to MyBP-C. (D) Two-color dSTORM super-resolution image of sarcomeres as in (C), labeled with Alexa Fluor–conjugated antibodies to MyBP-C and ryanodine receptors.

Mentions: Ventricular power generation involves the rapid release of calcium from the sarcoplasmic reticulum (SR) and diffusion of these ions through the sarcomere to activate the contractile machinery (Fig. 1A). Each heartbeat is initiated by an action potential that triggers the opening of ryanodine receptors (1) (calcium release channels in the terminal cisternae of the SR) that are located within nanometers of the Z-lines of each sarcomere (Fig. 1A). Calcium then binds to the troponin-tropomyosin regulatory complex to activate the actin-based thin filament so that myosin molecular motors, comprising the thick filaments, can interact with the thin filaments (Fig. 1A) to generate force and motion (2, 3). Because of the spatial organization of the calcium release channels and diffusion rates in the sarcomere, molecular modeling (4) and experimental evidence from elongated frog skeletal muscle (5) suggest that a spatiotemporal calcium gradient should exist along the length of each cardiac sarcomere that could lead to heterogeneity in excitation-contraction (E-C) coupling. Cardiac myosin-binding protein C (MyBP-C) (Fig. 1B), which is considered to be a potential activator of the thin filament (6–9), is located in a region of the sarcomere (that is, C-zone; Fig. 1A) that would experience such temporal delays in calcium concentrations. Therefore, we hypothesize that localization of MyBP-C to the C-zone may mitigate potential inhomogeneities in calcium activation.


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

Previs MJ, Prosser BL, Mun JY, Previs SB, Gulick J, Lee K, Robbins J, Craig R, Lederer WJ, Warshaw DM - Sci Adv (2015)

Sarcomeric organization and MyBP-C(A) Cardiac muscle sarcomere with interdigitating thick and thin filaments. MyBP-C localized to the C-zone, whereas the ryanodine receptors are localized in puncta (CRUs) along the Z-lines, forming the boundaries of each sarcomere. (B) Schematic diagram of cardiac MyBP-C’s Ig-like (oval) and fibronectin-like (rectangular) domains with four phosphorylation sites (P) in the M-domain and C0C3 fragment (dashed box) used in the 3D EM and in vitro motility experiments. (C) Negatively stained EM image of a sarcomere within a mouse ventricular myocyte labeled with antibodies to MyBP-C. (D) Two-color dSTORM super-resolution image of sarcomeres as in (C), labeled with Alexa Fluor–conjugated antibodies to MyBP-C and ryanodine receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380226&req=5

Figure 1: Sarcomeric organization and MyBP-C(A) Cardiac muscle sarcomere with interdigitating thick and thin filaments. MyBP-C localized to the C-zone, whereas the ryanodine receptors are localized in puncta (CRUs) along the Z-lines, forming the boundaries of each sarcomere. (B) Schematic diagram of cardiac MyBP-C’s Ig-like (oval) and fibronectin-like (rectangular) domains with four phosphorylation sites (P) in the M-domain and C0C3 fragment (dashed box) used in the 3D EM and in vitro motility experiments. (C) Negatively stained EM image of a sarcomere within a mouse ventricular myocyte labeled with antibodies to MyBP-C. (D) Two-color dSTORM super-resolution image of sarcomeres as in (C), labeled with Alexa Fluor–conjugated antibodies to MyBP-C and ryanodine receptors.
Mentions: Ventricular power generation involves the rapid release of calcium from the sarcoplasmic reticulum (SR) and diffusion of these ions through the sarcomere to activate the contractile machinery (Fig. 1A). Each heartbeat is initiated by an action potential that triggers the opening of ryanodine receptors (1) (calcium release channels in the terminal cisternae of the SR) that are located within nanometers of the Z-lines of each sarcomere (Fig. 1A). Calcium then binds to the troponin-tropomyosin regulatory complex to activate the actin-based thin filament so that myosin molecular motors, comprising the thick filaments, can interact with the thin filaments (Fig. 1A) to generate force and motion (2, 3). Because of the spatial organization of the calcium release channels and diffusion rates in the sarcomere, molecular modeling (4) and experimental evidence from elongated frog skeletal muscle (5) suggest that a spatiotemporal calcium gradient should exist along the length of each cardiac sarcomere that could lead to heterogeneity in excitation-contraction (E-C) coupling. Cardiac myosin-binding protein C (MyBP-C) (Fig. 1B), which is considered to be a potential activator of the thin filament (6–9), is located in a region of the sarcomere (that is, C-zone; Fig. 1A) that would experience such temporal delays in calcium concentrations. Therefore, we hypothesize that localization of MyBP-C to the C-zone may mitigate potential inhomogeneities in calcium activation.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute of Vermont, The University of Vermont, Burlington, VT 05405, 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.

No MeSH data available.


Related in: MedlinePlus