Abstract 18980: N-terminal Region of Cardiac Myosin Binding Protein-C Regulates Sarcomeric and Cardiac Function
Rationale: Cardiac myosin binding protein-C (cMyBP-C) is a trans-filament protein that can bind both the thick and thin filaments and regulate contraction. Previously we showed that decreased cMyBP-C phosphorylation is directly associated with catalytic cleavage of the first 271 residues of the N-terminal (N’) and, as a consequence, contractile dysfunction. This region has been shown to be largely responsible for the actin-myosin interacting properties of cMyBP-C and was postulated to regulate sarcomere sliding velocity. However, it is unknown whether it is necessary to regulate contractile function.
Hypothesis: N’-region of cMyBP-C is essential for sarcomeric and cardiac function.
Methods and Results: To determine the necessity of N’-region, we generated transgenic mice (C57BL/6) expressing a truncated 110kDa cMyBP-C lacking the first 271 amino acids (Tg110). Compared to non-transgenic litter-mates (NTG), Tg110 mice demonstrate high replacement levels of native cMyBP-C (>95%). Truncated cMyBP-C localized properly to the C-zone and there were no difference in cardiac sarcomere structure between Tg110 and NTG mice. Despite normal localization and sarcomere structure, Tg110 mouse hearts displayed overt chamber dilation and depressed ejection fraction as measured by echocardiography, with little evidence of fibrosis. Cardiac permeabilized myofilament preparations demonstrate depressed maximal force generation in Tg110 compared to NTG, with unchanged Ca2+ sensitivity and cooperativity. Interestingly, Tg110 myofilaments displayed increased rate of cross-bridge cycling, supporting the hypothesis that the N’-region is responsible for actin interaction and acts as a viscous load on myosin heads.
Conclusion: We show that the N’-region of cMyBP-C is indispensable for proper cardiac function. Further, we successfully demonstrate that cMyBP-C is a regulator of cardiac contractility and specifically fulfills that role via its N’-region.
Author Disclosures: D.W. Kuster: None. R.J. Khairallah: None. N. Witayavanitkul: None. D. Barefield: None. M. Kumar: None. S. Govindan: None. S. Mayandi: None. K. Lee: None. R. Craig: None. P.P. de Tombe: None. S. Sadayappan: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.