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

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $489,508

## Abstract

ABSTRACT:
The goal of this project is to understand how cardiac myosin binding protein-C (cMyBP-C) regulates heart
muscle contraction and how dysregulation of cMyBP-C causes systolic and diastolic dysfunction. Work from
the PI's lab over the past decade firmly established that cMyBP-C binds to thin (actin) filaments and activates
contraction in the same way as Ca2+ and strongly bound myosin cross-bridges. These discoveries
fundamentally challenged the preconception that cMyBP-C affects contraction exclusively via inhibition of thick
(myosin) filaments. Direct interactions of cMyBP-C with the thin filament can also adequately explain profound
effects of cMyBP-C to modulate both diastolic and systolic cardiac function. However, until now functional
effects due to cMyBP-C interactions with actin were purely hypothetical because there has been no way to
distinguish between effects of cMyBP-C binding to actin or myosin in working hearts. An additional problem is
a lack of complementary methods to selectively modify cMyBP-C in sarcomeres. Without this combination of
tools it has been impossible to target specific interactions with cMyBP-C binding partners in situ. Here we
decisively overcome these barriers by creating unique resources that allow us to functionally dissect cMyBP-C
interactions with the thin filament. Innovations include 2 new transgenic mouse models, each with a single
mutation in a highly conserved actin binding sequence that we identified in the regulatory M-domain. The
mutations either increase (L348P) or decrease (E330K) cMyBP-C binding to the thin filament. Preliminary data
from the mice suggest that cMyBP-C interactions with actin control fundamental timing of contraction and
relaxation because the L348P mutation increased the duration of systolic ejection and slowed diastolic
relaxation, while the E330K mutation decreased the duration of systole. Aim 1 of the proposed experiments will
use the L348P and E330K mice test the hypothesis that cMyBP-C binding to actin maintains thin filament
activation at the end of systole independent of declining activation by Ca2+ or strongly bound cross-bridges. In
Aim 2, we created a third unique mouse model, referred to as “Spy-C” mice, that allows us to replace N'-
terminal domains of cMyBP-C in sarcomeres in situ with any desired modification to probe function. In Aim 2
we will use the Spy-C system to test the hypothesis that sarcomere length dynamically regulates cMyBP-C
binding interactions with actin and we will further assess the impact of the middle domains (C3-C7) of cMyBP-
C and effects of HCM missense mutation hotspots in these domains for the first time. We will identify cMyBP-C
interacting partners in the sarcomere by labeling cMyBP-C N'-terminal domains using FRET based sensors.
The long-term impact of this work is that we will be able to selectively define the impact of cMyBP-C
interactions with the thin filament on systolic and diastolic cardiac function and identify new mechanisms...

## Key facts

- **NIH application ID:** 10155578
- **Project number:** 5R01HL080367-15
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Samantha P Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $489,508
- **Award type:** 5
- **Project period:** 2005-09-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155578

## Citation

> US National Institutes of Health, RePORTER application 10155578, Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction (5R01HL080367-15). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10155578. Licensed CC0.

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