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J Am Heart Assoc. 2016 Mar 15;5(3):e002836. doi: 10.1161/JAHA.115.002836.

Alterations in Multi-Scale Cardiac Architecture in Association With Phosphorylation of Myosin Binding Protein-C.

Author information

1
Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA.
2
Health Sciences Division, Department of Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL.
3
Division of Molecular Cardiovascular Biology, Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
4
Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA rjgilbert12@gmail.com.

Abstract

BACKGROUND:

The geometric organization of myocytes in the ventricular wall comprises the structural underpinnings of cardiac mechanical function. Cardiac myosin binding protein-C (MYBPC3) is a sarcomeric protein, for which phosphorylation modulates myofilament binding, sarcomere morphology, and myocyte alignment in the ventricular wall. To elucidate the mechanisms by which MYBPC3 phospho-regulation affects cardiac tissue organization, we studied ventricular myoarchitecture using generalized Q-space imaging (GQI). GQI assessed geometric phenotype in excised hearts that had undergone transgenic (TG) modification of phospho-regulatory serine sites to nonphosphorylatable alanines (MYBPC3(AllP-/(t/t))) or phospho-mimetic aspartic acids (MYBPC3(AllP+/(t/t))).

METHODS AND RESULTS:

Myoarchitecture in the wild-type (MYBPC3(WT)) left-ventricle (LV) varied with transmural position, with helix angles ranging from -90/+90 degrees and contiguous circular orientation from the LV mid-myocardium to the right ventricle (RV). Whereas MYBPC3(AllP+/(t/t)) hearts were not architecturally distinct from MYBPC3(WT), MYBPC3(AllP-/(t/t)) hearts demonstrated a significant reduction in LV transmural helicity. Null MYBPC3((t/t)) hearts, as constituted by a truncated MYBPC3 protein, demonstrated global architectural disarray and loss in helicity. Electron microscopy was performed to correlate the observed macroscopic architectural changes with sarcomere ultrastructure and demonstrated that impaired phosphorylation of MYBPC3 resulted in modifications of the sarcomere aspect ratio and shear angle. The mechanical effect of helicity loss was assessed through a geometric model relating cardiac work to ejection fraction, confirming the mechanical impairments observed with echocardiography.

CONCLUSIONS:

We conclude that phosphorylation of MYBPC3 contributes to the genesis of ventricular wall geometry, linking myofilament biology with multiscale cardiac mechanics and myoarchitecture.

KEYWORDS:

basic studies; echocardiography; genetically altered mice; heart failure; magnetic resonance imaging; quantitative modeling

PMID:
27068630
PMCID:
PMC4943261
DOI:
10.1161/JAHA.115.002836
[Indexed for MEDLINE]
Free PMC Article

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