CARDIAC MYOSIN BINDING PROTEIN-C ACTS AS A TUNABLE LOAD SENSOR TO REGULATE AFTERLOAD DEPENDENCE OF VENTRICULAR FUNCTION.

The sarcomeric protein cardiac myosin binding protein-C (cMyBP-C) binds myosin on thick filaments and regulates cardiac myocyte contraction. Our lab has reported that permeabilized cardiac myocytes lacking cMyBP-C generate greater power and show disproportionately fast sarcomere shortening velocities at high loads. Also, high resolution X-ray diffraction of cardiac trabeculae found that myosin cross-bridges in the cMyBP-C zone are the most active during loaded contractions. Together, these results implicate cMyBP-C as a potential molecular load sensor. We tested the hypothesis that cMyBP-C is a tunable load sensor that matches afterload and left ventricular (LV) performance. We compared afterload-dependence of LV power between isolated hearts from mice lacking cMyBP-C (KO) or transgenic mice expressing either wild-type (WT) (cMyBP-C WT), cMyBP-C carrying pseudo-phosphorylated cMyBP-C (cMyBP-C t3SD) or non-phosphorylatable cMyBP-C (cMyBP-C t3SA). cMyBP-C KO hearts exhibited minimal differences in LV power as a function of afterload from 40 mmHg to 60 mmHg. In contrast, cMyBP-C WT hearts exhibited relatively steep afterload dependence of LV power. We also tested whether load sensing is tunable by cMyBP-C phosphorylation. We observed steep afterload dependence of LV power in hearts carrying pseudo-phosphorylated cMyBP-C (cMyBP-C t3SD). Alternatively, hearts with non-phosphorylatable cMyBP-C (cMyBP-C t3SA) exhibited less afterload dependence of LV power. Thus, it appears cMyBP-C acts as a tunable load sensor that matches myofilament power with hemodynamics.