Abstract 303: Fast Skeletal Myosin Binding Protein-c Expression in Heart Failure

Abstract

Background: Heart failure is a devastating disease affecting nearly 5 million Americans. We recently identified the upregulation of fast skeletal myosin binding protein-C (fsMyBP-C) in models of heart failure. fsMyBP-C is a homologue of cardiac MyBP-C, which is normally expressed in the heart. This family of proteins regulate contractility by modulating thick and thin filament interactions. However, the functional role(s) of fsMyBP-C expression in the heart is unknown. Methods: To understand the role of fsMyBP-C expression in the heart, we generated cardiac specific transgenic mice expressing fsMyBP-C under the control of the alpha myosin heavy chain promoter. Mice underwent serial echocardiography to monitor cardiac function. Western blotting and qRT-PCR were performed to determine transgene expression levels. Additionally, fsMyBP-C localization in cardiomyocytes was established by immunofluorescence. Furthermore, to understand the temporal expression profiles of the MyBP-C homologues, we performed qRT-PCR on 9 muscle groups at different developmental stages in healthy mice. Results: qRT-PCR demonstrated an upregulation of the slow MyBP-C transcript in the developing heart, while fsMyBP-C transcript levels increased steadily following birth in WT mice. At 3 months of age, transgenic mice displayed a significant increase in ventricular dimensions compared to NTG littermates by echocardiography (LVID d : 3.72 ± 0.07 vs. 4.17 ± 0.09 mm, p<0.01; LVID s : 2.44 ± 0.09 vs. 2.81 ± 0.09, p<0.05), with no changes in wall thickness. This was accompanied by a 25% increase in stroke volume (p<0.01) and a 30% increase in cardiac output (p<0.05). fsMyBP-C correctly localized to the C-zone of the sarcomere. Furthermore, protein levels showed mild expression of fsMyBP-C, in line with the small upregulation seen in diseased hearts, while qRT-PCR confirmed overexpression of fsMyBP-C in the ventricles. Conclusion: Mice expressing fsMyBP-C in the heart display a mild hypertrophic phenotype at 3 months, with preserved function, possibly indicating compensated hypertrophy. Ongoing studies investigate cardiac function at later stages and cardiac specific conditional knockout of fsMyBP-C to determine the long-term effect of fsMyBP-C regulation in the heart.