# Molecular Basis of Left Ventricular Non-Compaction Mutations in Cardiac Myosin

> **NIH NIH F31** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2024 · $28,558

## Abstract

ABSTRACT:
Left ventricular non-compaction (LVNC), a rare but increasingly prevalent cause of cardiomyopathy stemming
from developmental arrest of myocardial compaction, was identified as a primarily genetic, independent
cardiomyopathy by the AHA in 2006 following debate due to its frequent association with variable degrees of
myocardial dysfunction and other congenital heart defects (CHD). Symptom heterogeneity has likely left many
cases undiagnosed, giving a lower estimation of its real impact as a cardiomyopathy. Congenital LVNC can
progress in severity throughout life contributing to decompensated heart failure and sudden cardiac death. Little
is known about the molecular mechanism(s) that lead to LVNC, but mutations in MYH7 (encoding human beta-
cardiac myosin) have been implicated as a putative genetic cause. Human beta-cardiac myosin (M2β) mutations
are known molecular triggers for heritable cardiomyopathies, typically impacting the motor protein’s intrinsic
motor properties and/or auto-inhibited state. Studies of cardiomyopathy mutations in M2β have demonstrated
that hypertrophic cardiomyopathy (HCM) is triggered by mutations that cause hyper-contraction and dilated
cardiomyopathy (DCM) is triggered by mutations that cause hypo-contraction. However, very few studies have
examined LVNC mutations and thus it is unclear how it falls on this genotype-phenotype spectrum. Examining
LVNC cardiac myosin mutations would enlighten us about the unique etiology and reveal important information
about myosin structure and function. We hypothesize that depressed monomeric ensemble force and/or an
increase in autoinhibited state stabilization could trigger severe hypo-contraction and tissue level
tension/force imbalances, leading to excessive trabeculation in LVNC. We conclude that additional
biophysical LVNC M2β mutant studies both in purified protein and cellular systems are required to
uncover common allosteric pathways altered in LVNC. Our goal is to investigate the impact of clinically
identified MYH7 LVNC mutations M362R and L655M on protein structure-function, mechanochemistry, and
ultimately pathogenic myocardial remodeling. M362R is in the loop 4 region of the motor domain known to play
an important role in head-head interactions, tropomyosin positioning, and actin binding. L655M may disrupt a
critical allosteric pathway leading to actin-activation of the power stroke and thus impair the transition into the
force generating states. This proposal will characterize two LVNC mutations selected based on the isolation of
LVNC from other forms of heritable cardiomyopathy and on their respective locations within myosin known to be
important for performance. We will utilize transient kinetic, novel applications of FRET biosensors and
analytical ultracentrifugation, and hiPSC-CM derived myofibril-based techniques to elucidate how these
mutations impair myosin function leading to LVNC pathogenic remodeling of the heart.

## Key facts

- **NIH application ID:** 10997486
- **Project number:** 1F31HL172616-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Skylar ML Bodt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $28,558
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997486

## Citation

> US National Institutes of Health, RePORTER application 10997486, Molecular Basis of Left Ventricular Non-Compaction Mutations in Cardiac Myosin (1F31HL172616-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10997486. Licensed CC0.

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