Abstract 376: Amino Terminal C0-C1f Region of Cardiac Myosin Binding Protein-C is Essential for Normal Cardiac Function
Rationale: Cardiac myosin binding protein-C (cMyBP-C) is a trans-filament protein that has been shown to regulate cardiac function via its amino terminal (N’) regions. However, it is unknown whether the first 271 residues (C0-C1f region) are necessary to regulate contractile function in vivo.
Hypothesis: The N’-region of cMyBP-C is critical for proper cardiac function in vivo.
Methods and Results: Transgenic mice with approximately 80% expression of mutant truncated cMyBP-C missing C0-C1f (cMyBP-C110kDa), compared to endogenous cMyBP-C, were generated and characterized at 3-months of age. cMyBP-C110kDa hearts had significantly elevated heart weight/body weight ratio, fibrosis, nuclear area and collagen content compared to hearts from non-transgenic (NTG) littermates. Electron microscopic analysis revealed normal sarcomere structure in cMyBP-C110kDa hearts but with apparently weaker cMyBP-C stripes. Furthermore, the ability of cMyBP-C to slow actin-filament sliding within the C-zone of native thick filaments isolated from NTG hearts was lost on thick filaments from cMyBP-C110kDa hearts. Short axis M-mode echocardiography revealed a significant increase in left ventricular (LV) internal diameter during diastole in cMyBP-C110kDa hearts. Importantly, cMyBP-C110kDa hearts displayed a significant reduction in fractional shortening compared to hearts from NTG littermates. We further observed a decrease in the thickness of the LV interventricular septum and free wall during systole in cMyBP-C110kDa hearts. Strain analysis using images acquired from ECG-Gated Kilohertz Visualization identified a significant deficit in global longitudinal strain in cMyBP-C110kDa hearts compared to NTG hearts.
Conclusion: The N’-region of cMyBP-C is indispensable for maintaining normal cardiac morphology and function and loss of this region promotes contractile dysfunction both at the molecular and tissue levels.
Author Disclosures: T.L. Lynch: 2. Research Grant; Modest; AHA Award Number: 15PRE22430028. D.W.D. Kuster: None. D. Barefield: None. M. Sivaguru: None. M.J. Previs: None. K. Lee: None. S. Govindan: None. R. Craig: None. D.M. Warshaw: None. S. Sadayappan: 2. Research Grant; Modest; AHA Award Number: 14GRNT20490025, NIH K02HL114749, NIH R01HL105826.
- © 2015 by American Heart Association, Inc.