The Role Of Cardiac Mybpc In Regulating Frank Starling Relationships

According to the Frank-Starling Relationship, elevations in end-diastolic volume progressively increase peak ventricular pressure and stroke volume in healthy hearts. This relationship is modulated by a number of physiological inputs and is often depressed in human heart failure. Emerging evidence suggests cardiac Myosin Binding Protein-C (cMyBP-C) may be intricate in regulating the Frank-Starling Relationship. For instance, transgenic animal studies have implicated both length dependence of Ca2+ sensitivity of force (Cazorla et al., 2006; Kumar et. al., 2015) and stretch activation (Mamidi et. al., 2016) are modulated by the phosphorylation state of cMyBP-C. We measured contractile properties across multiple spatial organization levels to discern the role of cMyBP-C and its phosphorylation in determining i) the sarcomere length dependence of force in cardiac myofilaments and ii) Frank-Starling relationships. For this study, we utilized WT mice, which are thought to have >50% phosphorylated cMyBP-C (Controls), as well as transgenic mice lacking cMyBP-C (KO), and transgenic mice expressing cMyBP-C having serine-273, −282, −302 mutated to aspartate on the null background to mimic constitutive PKA phosphorylation (cMyBP-C CT-t3SD mice). We observed reduced slopes and greater variability in sarcomere length-tension relationships in permeabilized cardiac myocyte preparations from cMyBP-KO mice. In contrast, length-tension relationships were steep and highly tuned in the myocyte preparations from cMyBP-C CT-t3SD animals. Also, the pre-load dependence of left ventricular power output was greatest in isolated hearts from cMyBP-C CT-t3SD mice. Furthermore, step-wise volume expansion during continuous echocardiographic imaging revealed Frank-Starling Relationships were diminished in cMyBP-C KO mice and steepest in cMyBP-C CT-t3SD animals. These results support the hypothesis that cMyBP-C and its post-translational modifications precisely tune sarcomere length dependence of myofibrillar force and power, and these regulatory processes translate across all spatial levels of organization to optimize beat-to-beat regulation of ventricular performance.