# Deciphering the role of Lmod2 in cardiac muscle and in dilated cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $585,796

## Abstract

PROJECT SUMMARY
Effective contractile force in muscle requires the proper assembly, regulation, and activation of actin-containing
thin filaments. Leiomodins (Lmods) are a family of actin-binding proteins that regulate assembly of actin
filaments through a single tropomyosin-binding and multiple actin-binding domains. We previously discovered
that both knockout and overexpression of the cardiac predominant isoform (Lmod2) alters the lengths of thin
filaments in vivo and results in cardiomyopathy. Our extensive preliminary data suggest that Lmod2 impacts
contractile function - independent of actin-thin filaments length regulation. With a plethora of unique
experimental tools in hand, the goal of this proposal is to definitively determine the mechanisms of how
mutations in LMOD2 lead to heart failure.
 It is becoming increasingly clear that the Lmod family of proteins play a critical role in muscle function;
mutations in any of the three LMOD isoforms lead to debilitating human diseases. In this proposal, we describe
the first known human mutation in LMOD2. This mutation leads to severe neonatal dilated cardiomyopathy. All
LMOD-linked diseases have the common underlying pathophysiology of severe muscle weakness due to
reduced contractility. Most of the disease-causing mutations in the LMOD gene family are nonsense or
frameshift mutations predicted to result in expression of truncated proteins. However, in nearly all cases of
disease little to no LMOD protein is expressed. Extensive preliminary data suggests that nonsense-mediated
mRNA decay underlies the loss of mutant LMOD2 protein, which we can restore using LMOD2-specific
antisense oligonucleotides.
 We hypothesize that Lmod2 is a multifunctional protein that influences cardiac contractility through
maintaining proper thin filament lengths and positively effecting activation of the thin filament. We propose a
multidisciplinary approach utilizing a unique combination of in vitro assays, patient-specific induced pluripotent
stem cell-derived cardiomyocytes (iPSC-CMs), and novel models of human disease to accomplish two Specific
Aims focused on determining: 1) the fundamental function(s) of Lmod2, particularly how Lmod2 regulates thin
filament assembly and what role it has in cardiac contractility, and 2) why human mutations in LMOD2 lead to a
lack of protein expression, how loss of protein leads to disease, and whether restoring full-length or truncated
LMOD2 can prevent (rescue) the onset of cardiomyopathy. Elucidating the in vivo function(s) of Lmod2 will
provide critical missing links in our understanding of muscle contraction. In addition, these studies will have a
broad impact on understanding the etiology and potential treatments of a spectrum of diseases that result from
mutations in the LMOD family of genes, as well as other diseases that involve nonsense-mediated mRNA
decay of essential proteins.

## Key facts

- **NIH application ID:** 10121734
- **Project number:** 2R01HL123078-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Carol C Gregorio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $585,796
- **Award type:** 2
- **Project period:** 2015-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121734

## Citation

> US National Institutes of Health, RePORTER application 10121734, Deciphering the role of Lmod2 in cardiac muscle and in dilated cardiomyopathy (2R01HL123078-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10121734. Licensed CC0.

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