The Role Of Cmybp-C In Regulating The Frank-Starling Relationship

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. 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 power 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 or alanine on the null background to either mimic constitutive PKA phosphorylation (cMyBP-C CT-t3SD) or non-phosphorylated cMyBP-C (cMyBP-C CT-t3SA). We observed enhanced length-dependence of power output in myocyte preparations from cMyBP-C CT-t3SD animals. In contrast, length-dependence of power as well as absolute power output were decreased in permeabilized myocyte preparations from cMyBP-C CT-t3SA mice. Interestingly, absolute power and normalized power output were increased in myocytes from cMyBP-C KO mice, however, length-dependence of power was diminished, indicating loss of myofilament regulation. 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. The results support the hypothesis that cMyBP-C and its post-translational modifications tune sarcomere length dependence of myofibrillar force and power, and these regulatory mechanisms translate across spatial levels of organization to optimize beat-to-beat regulation of ventricular performance.