Dual filament control of myocardial power and hemodynamics

University Of Missouri-Columbia, Columbia MO

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Abstract

Abstract The heart’s pumping capacity is determined by myofilament loaded shortening and power output since the ventricles always work against an afterload to eject blood. The molecular mechanism to explain afterload dependence of ventricular function has eluded cardiac muscle physiologists and cardiologists for decades, and this mechanism could be pivotal for novel small molecule therapies aimed to help heart failure patients. In the previous cycle of the project, the MPI team (a) collectively published 33 peer-reviewed papers, (b) discovered a thin filament mechanism to enhance power reserve capacity in myofilaments from human failing hearts, (c) demonstrated phosphorylation-dependent MyBP-C induced interfilamentary drag, (d) integrated our FiberSim and FiberVent computational models, and (e) adapted cMyBP-C’s putative regulatory functions to our FiberSim model to derive new hypotheses for the current proposal. The new objectives are to (i) use biochemical, biophysical, and transgenic tools to discern cMyBP-C’S role in regulating myofilament power and afterloaded cardiac contractions and (ii) integrate these control mechanisms into our multi-scale computational model that can predict how sarcomere-level modifications impact hemodynamics. The experimental approach is strategically designed to address three independent yet complementary aims. Aim 1 will test the novel hypotheses that cMyBP-C is the load sensor, phosphorylation of cMyBP-C enhances the load-dependence, and these effects translate to ventricular function. Experiments will manipulate cMyBP-C’s phosphorylation state to optimize the load dependence of myofilament power and the afterload dependence of ventricular performance. Aim 2 tests the hypothesis that cMyBP-C tunes load dependence by its N-terminal position, which is modulated by its phosphorylation state using innovative FRET and fluorescent polarization methodologies. In Aim 3, computer models of sarcomere and organ-level function will be deployed to test molecular mechanisms of load-dependent contraction and hemodynamics. This work extends beyond the sarcomere and has the potential to identify high-value therapeutic targets to optimize ventricular performance in heart failure patients.