# Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $622,935

## Abstract

TITLE: Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction
ABSTRACT: The overall goal of this project is to understand how cardiac myosin binding protein-C (cMyBP-C)
regulates heart muscle contraction and relaxation. cMyBP-C is a critical regulator of cardiac function, with
dysfunction of cMyBP-C commonly occurring in heart failure and mutations in cMyBP-C being the most common
genetic cause of HCM. However, the regulatory effects of cMyBP-C are complex and most likely involve dynamic
interactions with both thick (myosin containing) and thin (actin containing) filaments, making it challenging to sort
out what are likely to be reciprocal or interrelated effects of cMyBP-C on each filament. To overcome these and
other challenges, we recently developed a novel method that allows us to rapidly remove and replace (“cut and
paste”) cMyBP-C at its endogenous position in sarcomeres, thus affording us the opportunity to quickly test
cMyBP-C effects on both filament systems. In Aim 1 we will test the functional significance of the “middle
domains” of cMyBP-C which were recently implicated as regulators of thick filament relaxation by stabilizing the
“interacting heads motif” conformation of myosin on the thick filament as well as novel regulators of cMyBP-C
function including Ca2+-Calmodulin (CaM) that we show in exciting new preliminary data may regulate cMyBP-C
binding to the thin filament. Because HCM mutations and posttranslational modifications (PTMs) also occur in
the middle domains and have been correlated with diastolic dysfunction we will also test effects of selected
mutations and PTMs in these domains. Experiments will include measurements of steady state force in
permeabilized cardiomyocytes as well as rates of activation and relaxation in myofibrils and the activation state
of thick filaments determined by myosin DRX/SRX ratios. In Aim 2 we will use the cut and paste approach
combined with X-ray diffraction to determine structural effects of cMyBP-C on the activation/relaxation states of
thick and thin filaments in sarcomeres. Specifically, we will test the hypothesis that C-links between thick and
thin filaments modulate the on/off states of thick and thin filaments and contribute to thick filament activation in
response to passive stretch or active load. Results from these studies will provide new insights into how cMyBP-
C regulates heart function during health and disease.

## Key facts

- **NIH application ID:** 10881371
- **Project number:** 2R01HL080367-16A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Samantha P Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $622,935
- **Award type:** 2
- **Project period:** 2005-09-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881371

## Citation

> US National Institutes of Health, RePORTER application 10881371, Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction (2R01HL080367-16A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881371. Licensed CC0.

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