# Cardiac Myosin Binding Protein-C in Development and Reversal of Heart Failure

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2021 · $491,894

## Abstract

Heart failure (HF) afflicted 6.5 million Americans in 2017, carries 5-year mortality of ~50%, and will likely increase
to > 8 million by 2030. The lack of significant improvement in mortality for the last 46 years, the reality of needing
to discontinue effective medications due to hypotension in heart failure with reduced ejection fraction (HFrEF),
and the paucity of effective treatment for heart failure with preserved ejection fraction (HFpEF) combine to
suggest that new treatments are needed. Cardiac myosin binding protein-C (cMyBPC) resides on the thick
filament of the heart muscle. Phosphorylation of cMyBPC at its M-domain increases cross-bridge cycling rate.
Because increasing cross-bridge cycling rate can improve both contractility and lusitropy, we hypothesize that
phosphorylation of cMyBPC provides a novel central mechanism that can prevent and treat HF due to different
causes. Using mouse models that mimic de-phosphorylated and phosphorylated cMyBPC at 3 serine (S) sites
in the M-domain, we recently discover that cMyBPC phosphorylation mitigates both aged-related development
of HFpEF and trans-aortic constriction (TAC) surgery induced HFrEF, as seen by improved survival and better
preservation of diastolic function. Thus, cMyBPC phosphorylation holds potential to treat both HFrEF and
HFpEF. However, we find evidence that 2 new S phosphorylation sites outside our study of 3 S sites add
significant functional effects. Consequently, we have made 2 new knock-in mouse models to include the new
sites for elucidating the effects of maximally phosphorylated cMyBPC(5SD) and dephosphorylated cMyBPC(5SA)
M-domain. We also find evidence that pressure stress can activate focal adhesion kinase (FAK) to phosphorylate
tyrosine (Y) residue(s) in cMyBPC. This discovery leads to a new supporting hypothesis that pressure stress
triggers FAK to phosphorylate cMyBPC to increase contractility as a compensatory response. With these
discoveries in mind, we intend to determine the efficacy of maximal M-domain phosphorylation and elucidate the
novel FAK-cMyBPC mechanism. Aim #1: Determine the efficacy and companion mechanisms of phosphorylated
cMyBPC to preserve cardiac function under HF inducing conditions of aging, pressure stress, and obesity. We
will challenge mice with 2-yr aging, TAC, or high fat diet. We will use a combination of functional and biochemistry
techniques to determine the underlying mechanisms. Ability of cMyBPC(5SD) mouse to resist deterioration and
effectiveness of using cMyBPC(5SD) gene therapy to reverse failing WT hearts will quantify the efficacy of cMyBPC
phosphorylation for prevention and treatment respectively. Aim #2: Elucidate signaling mechanism and
functional results of pressure stress induced tyrosine phosphorylation of cMyBPC. We will identify Y site(s),
confirm FAK-cMyBPC interaction, and elucidate effects of FAK phosphorylating cMyBPC on models ranging
from intact papillary muscle to new knock-in mouse. Impact: Efficacy results...

## Key facts

- **NIH application ID:** 10070645
- **Project number:** 5R01HL145534-03
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Carl Wei-Chan Tong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,894
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070645

## Citation

> US National Institutes of Health, RePORTER application 10070645, Cardiac Myosin Binding Protein-C in Development and Reversal of Heart Failure (5R01HL145534-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10070645. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*