title: Alterations in Multi-Scale Cardiac Architecture in Association With Phosphorylation of Myosin Binding Protein-C.
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))).
  
  
  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.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA.
authors.forename: Erik N
authors.initials: EN
authors.lastname: Taylor
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hoffman
authors.affiliation: Health Sciences Division, Department of Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL.
authors.forename: David Y
authors.initials: DY
authors.lastname: Barefield
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA.
authors.forename: George E
authors.initials: GE
authors.lastname: Aninwene
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA.
authors.forename: Aurash D
authors.initials: AD
authors.lastname: Abrishamchi
authors.affiliation: Health Sciences Division, Department of Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Lynch
authors.affiliation: Health Sciences Division, Department of Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL.
authors.forename: Suresh
authors.initials: S
authors.lastname: Govindan
authors.affiliation: Division of Molecular Cardiovascular Biology, Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.affiliation: Division of Molecular Cardiovascular Biology, Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.affiliation: Health Sciences Division, Department of Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA rjgilbert12@gmail.com.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D007090:Image Interpretation, Computer-Assisted; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010641:Phenotype; D010766:Phosphorylation; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D016277:Ventricular Function, Left; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: basic studies; echocardiography; genetically altered mice; heart failure; magnetic resonance imaging; quantitative modeling