# Myofilaments as regulators of heart function in disease

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $551,404

## Abstract

Abstract
Ischemic cardiomyopathy and heart failure are the leading causes of combined morbidity and mortality in
humans. Herein, sarcomere dysfunction has a central role in disease pathogenesis. The sarcomere is the
essential functional unit of cardiac muscle, directly responsible for the pumping action of the heart. The cardiac
sarcomere is a multimeric contractile apparatus consisting of a thin myofilament-based allosteric regulatory
complex together with the myosin-based thick myofilament that generates force. Interlacing myofilaments
operate in synchrony to regulate and generate the forces necessary for heart performance. Beat-to-beat control
of cardiac sarcomere activation refers to the status of the thin filament regulatory system in controlling the degree
to which contraction is turned on and off during a twitch. Disruption in sarcomere function underlies the basis for
numerous forms of acquired and inherited heart diseases affecting millions of people in this country. Thus, focus
here on mechanistic insights into sarcomere regulation underscores the major health relevance of this proposal.
Recently, emerging results have come to the fore positing synergistic inter-myofilament regulatory signaling
mechanisms, including a new role of myosin cross-bridge ON/OFF states in controlling muscle contraction.
Building on our sarcomere activation innovations featuring single unloaded cardiac myocytes, we have made a
breakthrough methodological advance, permitting real-time recordings of sarcomere activation in intact cardiac
muscle under physiological load. This system is capable of detecting, by intramolecular FRET, multiple
myofilament activating ligands during the physiological time course of a single twitch contraction in intact cardiac
muscle under load. Guiding hypothesis: During physiologically relevant twitch contractions under load, thin
filament activation is controlled dynamically by multiple synergistic inter-myofilament regulatory inputs, including
TnC bound Ca2+, TnI switch domain-TnC interaction, OFF to ON state myosin cross-bridges, and MyBP-C in live
cardiac muscle. This proposal aims to investigate inter-myofilament signaling by altering the TnI molecular switch
mechanism during the physiological time-course of a single cardiac twitch in live cardiac muscles under load; to
investigate the mechanism of inter-myofilament signaling during the cardiac twitch contraction in live intact
cardiac muscles by modification in myosin cross-bridges; and to investigate the role MyBP-C in inter-myofilament
signaling during physiological twitch contractions in intact cardiac muscles. Enabled by our innovative approach,
the new insights into inter-myofilament signaling mechanisms gained here will significantly impact our
understanding of cardiac function. In turn, this provides the essential foundation to guide new therapeutic
discovery for the diseased heart by leveraging the sarcomere as an excellent target for developing new
treatments and thera...

## Key facts

- **NIH application ID:** 10364296
- **Project number:** 2R01HL132874-05A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** JOSEPH Mark METZGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $551,404
- **Award type:** 2
- **Project period:** 2017-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364296

## Citation

> US National Institutes of Health, RePORTER application 10364296, Myofilaments as regulators of heart function in disease (2R01HL132874-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10364296. Licensed CC0.

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