# Multi-scale Analysis of the Role of Skeletal Muscle Actin Mutations in Dilated Cardiomyopathy

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2024 · $171,811

## Abstract

Project abstract
There are two main objectives for this 5-year career development plan: 1) define the role and mechanistic basis
of skeletal muscle actin mutations in dilated cardiomyopathy (DCM), and 2) transition the principal investigator
(PI) to independence through professional and scientific mentorship. Despite current therapies, many patients
with DCM progress to end stage heart failure possibly due to a lack of treating changes in contractility which
needs further exploration. The basis of all contraction in cardiac and skeletal muscles is myosin pulling on actin
filaments. Skeletal muscle actin is the minor actin isoform in the heart, and it has never been mechanistically
explored in DCM. In this proposal, the PI establishes a multiscale experimental platform that utilizes biochemical,
biophysical, and in vivo methods to robustly study the effects of the skeletal muscle actin mutation R256H on
heart and skeletal muscle. The PI previously found that R256H exceptionally associates with DCM without
skeletal myopathy unlike all other skeletal muscle actin mutations. His preliminary data demonstrates that R256H
has a dominant negative effect on contractility only in the presence of the actin-binding proteins troponin and
tropomyosin which is a novel mechanism that was discovered using a new technique of recombinant actin
purification created by the PI. He also establishes that R256H causes hypcontractility in human cardiomyocytes
and mouse hearts. He hypothesizes that R256H causes DCM without skeletal myopathy due to tissue-specific
expression of different isoforms of troponin and tropomyosin. This hypothesis will be tested by elucidating the
biochemical and structural effects of R256H in the context of cardiac and skeletal muscle troponin and
tropomyosin (Aim 1), defining the effects of R256H on cardiac and skeletal muscle cells and engineered tissues
(Aim 2), and analyzing the effects of R256H on cardiac and skeletal muscles of mice (Aim 3). Completing these
aims will establish the role of skeletal muscle actin mutations in DCM for the first time and create a multiscale
platform to study additional skeletal muscle actin mutations in cardiomyopathy for the PI’s first R01. Moreover,
with guidance of a formal mentoring committee, the PI will complete a curriculum that will build his biochemistry
and biophysics knowledge and techniques, teach him cryoEM structural analysis to connect structure to function,
and expand his understanding of cardiac and skeletal muscle disease modeling in animals. Finally, he will
improve his professional, logistical, and educational skills to fully transition to an independent investigator and
productive member of the scientific community capable of training future physician-scientists.

## Key facts

- **NIH application ID:** 10863630
- **Project number:** 1K08HL173569-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Ankit Garg
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $171,811
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863630

## Citation

> US National Institutes of Health, RePORTER application 10863630, Multi-scale Analysis of the Role of Skeletal Muscle Actin Mutations in Dilated Cardiomyopathy (1K08HL173569-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10863630. Licensed CC0.

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