Computer modeling of myosin binding protein C and its effects on cardiac contraction

Case Western Reserve University, Cleveland OH

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Abstract

ABSTRACT This collaboration develops a comprehensive mathematical model of phosphorylation-dependent cardiac myosin binding protein C (cMyBP-C) regulation. The resulting model will be leveraged to predict how to best manipulate cMyBP-C phosphorylation to prevent or reverse contractile dysfunction in heart failure with reduced, or preserved ejection fraction. Recent attempts to treat cardiac disease by modifying myofilament-level function have been mostly disappointing. The main problem is that it has been difficult to enhance contraction without compromising relaxation, and vice versa. In vivo, of course, autonomic control can enhance both contraction and relaxation at the same time. During exercise, for example, the heart contracts more forcefully and it also relaxes faster to allow time for the ventricles to fill as heart rate increases. While numerous mechanisms contribute to this behavior, cMyBP-C is one of the main sarcomere-level effectors. It’s therefore possible that cMyBP-C could be strategically manipulated to create innovative new treatments for cardiac disease. The main barrier to developing these treatments is that cMyBP-C’s function is complex and regulated by at least 9 phosphorylation residues. The functional roles of the individual residues are not equivalent and the large number of potential combinations means that approaches based solely on cell and animal-based experiments are impractical. This challenge will be overcome by developing computational models that can capture and predict cMyBP-C’s complex impact on contractile function at both the sarcomere and whole organ levels. The multidisciplinary team comprises three experienced investigators with complementary skills: Julian Stelzer, PhD, Kenneth Campbell, PhD, and Brett Colson, PhD. The proposal has 3 Aims: Aim 1 combines high-throughput screens and computer modeling to predict cMyBP-C phospho-variants that enhance contraction and relaxation. Aim 2 tests these predictions in mice using AAV9 gene delivery. Aim 3 determines whether phospho-variants of cMyBP-C can rescue contractile function in mice and in samples of myocardium isolated from patients with disease. The proposal is innovative and advances understanding of cMyBP-C biology and clinical translation. The team’s commitment to sharing open-source code and experimental data will benefit research focused on heart failure.