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 the afterload dependence of LV power between isolated hearts from mice lacking cMyBP-C knockout (KO) or transgenic mice expressing either wild-type (cMyBP-C WT), cMyBP-C carrying pseudo-phosphorylated cMyBP-C (cMyBP-C t3SD), or nonphosphorylatable cMyBP-C (cMyBP-C t3SA). cMyBP-C KO hearts exhibited minimal differences in LV power as a function of afterload from 40 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 nonphosphorylatable 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.NEW & NOTEWORTHY The afterload dependence of left ventricular (LV) power exhibited a continuum that depended on the state of the sarcomeric cMyBP-C. Afterload dependence of LV power was least in hearts without cMyBP-C KO, intermediate in hearts with nonphosphorylated cMyBP-C, more with wild-type cMyBP-C, and greatest in hearts with phosphomimetic cMyBP-C. Thus, it appears cMyBP-C acts as a tunable load sensor that matches myofilament power with hemodynamics.