# Mechanochemistry of myosin mutations that cause cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $487,243

## Abstract

Project Summary
Hypertrophic cardiomyopathy (HCM) is a prevalent genetic cardiac disease affecting 1 in every 300-500 people.
The disease is characterized by left ventricular hypertrophy, cardiomyocyte disarray, and interstitial fibrosis
resulting in impaired diastolic function often with preserved or enhances systolic function. Dilated
cardiomyopathy (DCM) has a similar occurrence and is characterized by thinning of one or both ventricular walls
producing insufficient systolic function and diminished ejection fraction, hallmarks of a failing heart. Genetic
mutations in sarcomere proteins have been identified to be associated with HCM and DCM, with mutations in -
cardiac myosin (MYH7) strongly implicated as drivers of both conditions. A widely cited model relating myosin
function to disease proposes that HCM arises from myosin mutations that enhance activity yielding
hypercontractile myocytes, whereas DCM arises from loss-of-function mutations that diminish activity yielding
hypo-contractility. Contractile abnormalities are proposed to be due to MYH7 gene mutations that affect ATPase
activity, velocity, force production, the number or availability of motor domains, and thin filament activation. These
molecular changes ultimately affect power output in a manner that impacts tissue architecture,
electrophysiological signaling, and cardiac performance. Emerging research has provided examples that do not
fit clearly into the prevailing model. For example, HCM mutations with decreased activity have been described
in molecular assays and at the level of isolated myofibrils. To delineate the mechanisms by which myosin
mutations lead to HCM and DCM, it is important to determine how changes in protein sequence lead to changes
in activity at both the molecular and ensemble levels. We selected specific HCM and DCM mutations that are
predicted to affect the mechanochemistry of the myosin motor. Our goal is to determine the effect of these
mutations on myosin activity, and to test whether the HCM gain-of-function and DCM loss-of-function paradigm
holds. We will utilize biochemical and biophysical approaches to assess the effect of mutations on the activity of
single motors and regulated filament assemblies. Aim 1 will determine the biochemical and mechanical effects
of key HCM and DCM mutations in human β-cardiac myosin. We will measure the ensemble kinetics and motility
using biochemical and gliding assays. Changes in unitary forces, step-size, and force dependent kinetic steps
will be measured using single molecule optical-trapping. Aim 2 will determine the effect of HCM/DCM mutations
on heterogenous myosin assembles and thin filament activation. We will examine the effect the regulation of
single molecules within a regulated system, and we will construct a myosin nanomachine using DNA origami
that mimics cardiac muscle. We will use regulated thin filaments and myofilaments containing defined ratios of
WT and mutant myosin. We expect that our approach will...

## Key facts

- **NIH application ID:** 10230396
- **Project number:** 1R01HL157997-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** YALE E GOLDMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $487,243
- **Award type:** 1
- **Project period:** 2021-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230396

## Citation

> US National Institutes of Health, RePORTER application 10230396, Mechanochemistry of myosin mutations that cause cardiomyopathy (1R01HL157997-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10230396. Licensed CC0.

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