Effect of Mutations in cMyBP-C on Sarcomere Mechanical Function

Abstract

A significant number of cardiac myopathies in children and adults are caused by mutations in the cMyBP-C gene. In disease, cardiac output is compromised by altered cardiac muscle fiber contractility due to modulated interactions between cMyBP with actin or with S2. Comparative measurements in WT and knockout mice (cMyBP-C-/-) muscle fibers have showed increased isotonic shortening velocity, power output and rate of force redevelopment in absence cMyBP-C. Thus, change of only a few amino acids in mutant cMyBP-C, especially in regions rich with phosphorylation sites, may cause significant change in dynamics of muscle contractility. Comparison of measured sliding velocities of actin filaments over the regions of myosin filament with and without cMyBP-C in motility assays have provided molecular insight how these structural changes alter the kinetics of the interactions of cMyBP-C with myosin and actin filaments. We used a multi-scale, computational modelling platform, MUSICO, (MUscle SImulation COde) to assess the effect of cMyBP-C mutations on sarcomere contraction. This platform includes explicit 3-D sarcomere structures, extensible actin and myosin filaments, various models for the actomyosin cycles, thin filament regulation via a continuous flexible chain (CFC) model and now cMyBP-C using the kinetic parameters for dynamically forming and disrupting connections between cMyBP-C and actin, derived from the motility studies. We compared the model predictions between different mutations and the corresponding mechanical experiments. The predictions from cMyBP-C sarcomeric model showed significant differences between the mutants, and closely followed observations. This results allow the quantitative evaluation of the role of cMyBP-C in the regulation of sarcomere structure and function, the development of a multi-scale myoarchitectural representation of disease phenotype and the creation of a novel diagnostic and prognostic methodology for tracking disease progression in patients.Supported by: R01s AR048776 and DC 011528