Alterations in multi-scale cardiac architecture in association with phosphorylation of myosin binding protein-C

Erik N. Taylor, Matthew P. Hoffman, David Yeomans Barefield, George E. Aninwene, Aurash D. Abrishamchi, Thomas L. Lynch, Suresh Govindan, Hanna Osinska, Jeffrey Robbins, Sakthivel Sadayappan, Richard J. Gilbert*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 phosphoregulatory serine sites to nonphosphorylatable alanines (MYBPC3AllP-/(t/t)) or phospho-mimetic aspartic acids (MYBPC3AllP+/(t/t)). Methods and Results-Myoarchitecture in the wild-type (MYBPC3WT) 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 MYBPC3AllP+/(t/t) hearts were not architecturally distinct from MYBPC3WT, MYBPC3AllP-/(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.

Original languageEnglish (US)
Article numbere002836
JournalJournal of the American Heart Association
Volume5
Issue number3
DOIs
StatePublished - 2015

Keywords

  • Basic studies
  • Echocardiography
  • Genetically altered mice
  • Heart failure
  • Magnetic resonance imaging
  • Quantitative modeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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