# Fast myosin binding protein-C and cardiac contractility in heart failure

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $405,000

## Abstract

PROJECT SUMMARY: Heart failure (HF) is a complex clinical syndrome and a predominant cause of
mortality in adults. The overall objective of this renewal is to continue to elucidate the mechanism of action
of the myosin binding protein-C (MyBP-C) family of proteins on cardiac function. MyBP-C proteins regulate
contractile structure and function in both cardiac and skeletal muscles. The present proposal is focused on
defining the role of one of the MyBP-C proteins, fast myosin binding protein-C (fMyBP-C), as a negative
regulator of cardiac contractility. fMyBP-C is minimally expressed at baseline in the heart but is significantly
increased in the cardiomyocytes during HF. In the pilot studies, a novel transgenic mouse that expresses
fMyBP-C (fMyBP-CTg) specifically in cardiomyocytes and at levels similar to those observed in HF develops
cardiac hypertrophy, decreased maximal force and reduced myofilament Ca2+ sensitivity. In contrast,
homozygous fMyBP-C knockout (fMyBP-CKO) mice, when challenged with transverse aortic coarctation
(TAC)-induced pressure overload, shows significantly improved cardiac function, compared to controls.
Furthermore, in vitro studies revealed that fMyBP-C negatively modulates cardiomyocyte contractility by
increasing super-relaxed state of myosin, actomyosin interactions and thin filament activation. However,
the molecular mechanisms underlying the regulation of fMyBP-C and, in turn, its impact on
sarcomere function, are completely unknown.
 On the basis of the preliminary findings, our central hypothesis is that fMyBP-C upregulation
reduces cardiac function during HF by reducing actomyosin interactions, preventing thin and thick filament
interactions and decreasing the rate of force generation, resulting in contractile dysfunction and HF.
SPECIFIC AIM 1 will use a novel fMyBP-CTg mouse model to determine the sufficiency of fMyBP-C
expression in the cardiomyocytes in reducing cardiac contractility, actomyosin interactions and cross-
bridges and developing HF, compared to controls, including cMyBP-C transgenic and null mice. Using the
fMyBP-CKO mice, SPECIFIC AIM 2 will define the necessity of fMyBP-C to exacerbate (TAC)-induced
pressure overload HF using fMyBP-CKO mice, compared to controls. In the same aim, a novel Mybpc2-
mScarlet (fluorescence) knock-in mouse model will be used to fate map fMyBP-C expression during TAC-
induced pressure overload. Using these mouse models, SPECIFIC AIM 3 will elucidate the molecular
mechanism(s) underlying reduced cardiac contractility using cardiomyocytes from the fMyBP-CTg and
fMyBP-CKO mice, as well as recombinant proteins and chimeras of cMyBP-C/fMyBP-C, on various
biophysical, biochemical and functional studies in vitro, compared to wild-type controls. Together, these
studies will determine the necessity and sufficiency of fMyBP-C to negatively regulate inotropy and cause
HF. The results will lead to the identification of potential therapeutic targets to treat HF.

## Key facts

- **NIH application ID:** 10382669
- **Project number:** 2R01HL105826-09
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Sakthivel Sadayappan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,000
- **Award type:** 2
- **Project period:** 2011-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10382669

## Citation

> US National Institutes of Health, RePORTER application 10382669, Fast myosin binding protein-C and cardiac contractility in heart failure (2R01HL105826-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10382669. Licensed CC0.

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