Abstract 17263: Cardiac Myosin Binding Protein-C Phosphorylation Mitigates Pressure-Overload Heart Failure Despite Alterations in Calcium Handling Academic Article uri icon


  • Heart failure with reduced ejection (HFrEF) fraction exhibits both systolic and diastolic dysfunctions; therefore, treatments that improve contractility and lusitropy will be helpful. Cardiac myosin binding protein-C (cMyBP-C), which is a thick filament protein, can increase rate of cross-bridge cycling by its phosphorylation status to enhance contractility and lusitropy. Consequently, we hypothesized that cMyBP-C phosphorylation mitigates HFrEF by preserving systolic and diastolic functions. We tested our idea by challenging WT cMyBP-C(tWT), phosphorylation-deficient cMyBP-C(t3SA):S273A/S282A/S302A, and phosphorylation-mimetic cMyBP-C(t3SD):S273D/S282D/S302D mouse models with trans-aortic constriction (TAC) to induce pressure-overload HFrEF. Survival at 5 weeks showed notable differences (tWT 75.66.7% n=41, t3SA 53.46.7% n=68, t3SD 92.14.4% n=38, p=0.00037). Serial echocardiography showed that cardiac structure and function deteriorated for all mouse models. In comparison to tWT at post-TAC week-5, t3SA demonstrated ventricular dilation and reduced ejection fraction (EF); conversely, t3SD exhibited better preservation of diastolic function (smaller E/Ea, where E=blood flow Doppler and Ea=tissue Doppler of peak myocardial relaxation velocity). Electrically paced intact papillary muscles from t3SA and t3SD demonstrated slower intracellular calcium decay (smaller decay rate constant kCa). Western blotting showed: (1) decreased calcium-ATPase (SERCA2a) expression in t3SA and t3SD, (2) lowest ryanodine receptor (RyR2) expression in t3SD, and (3) decreased calcium calmodulin kinase-2 phosphorylation (pCaMK2) only in t3SD. These calcium handling protein alterations likely prevented stronger rescue by cMyBP-C phosphorylation mimetic. Thus, cMyBP-C phosphorylation mimetic mitigated TAC-induced HFrEF (better survival and preservation of diastolic function) despite depression of calcium handling proteins.

published proceedings

  • Circulation

author list (cited authors)

  • Liu, Y., Rosas, P. C., Abdalla, M. I., Duonge, K. W., Kidwell, D. T., Dusio, G. F., & Tong, C. W.

citation count

  • 0

complete list of authors

  • Liu, Yang||Rosas, Paola C||Abdalla, Mohamed I||Duonge, Kevin W||Kidwell, David T||Dusio, Giuseppina F||Tong, Carl W

publication date

  • November 2015