# Improving cell membrane repair to treat muscular dystrophy

> **NIH NIH F31** · OHIO STATE UNIVERSITY · 2022 · $41,552

## Abstract

Project Summary
Duchenne Muscular Dystrophy (DMD) is a fatal degenerative muscle disease caused by mutations in the X-
linked dystrophin gene. DMD is the most prevalent form of muscular dystrophy with an incidence of 1:5,000
live male births. Dystrophin mutations lead to the loss of protein expression and compromised sarcolemmal
membrane integrity. Injury from mechanical stress often leads to muscle fiber death that eventually
overwhelms the regenerative capacity of the muscle. Repeated injury severely reduces skeletal muscle
strength contributing to early death by the second to fourth decade of life. Current treatment options can
prolong survival and improve quality of life; however, they are not curative. Therefore, there remains a need for
novel therapies that target the molecular mechanisms underlying disease pathology. Previous studies
determined that the tripartite motif protein 72/mitsugumin 53 (TRIM72/MG53) is essential for proper cell
membrane repair in skeletal and cardiac muscle through its binding of phosphatidylserine (PS). Loss of MG53
function has been associated with the development of muscular dystrophy and increased susceptibility to
cardiac injury. MG53 is a muscle-enriched TRIM family E3 ubiquitin ligase protein that our laboratory
previously reported can increase membrane repair by overexpression or by exogenous application of
recombinant MG53 (rhMG53) to ameliorate disease pathology in multiple models of muscular dystrophy. This
fellowship project aims to interrogate the role of rhMG53 protein domains in this observed effect on membrane
repair. My preliminary data suggest that the E3 ubiquitin ligase activity is not required for the enhanced
membrane repair phenotype. This observation supports the hypothesis that the canonical TRIM E3 ubiquitin
ligase activity of MG53 is not required for therapeutic membrane repair capacity, therefore therapeutic effects
may be achieved by compact versions of the MG53 protein that can bind PS. In this fellowship application I
propose to test this hypothesis using three specific and independent aims. Aim 1 screens rhMG53 mutant
protein constructs to identify rhMG53 protein domains that are essential for membrane repair. Aim 2 defines
the mechanistic role of phosphatidylserine binding to rhMG53 by identifying protein domain binding partners.
Aim 3 evaluates the therapeutic potential of identified rhMG53 mutant protein constructs when exogenously
delivered to intact muscle fibers ex vivo. These studies will provide an excellent training experience by
elucidating previously uncharacterized MG53 protein interactions that will enable the development of novel
protein therapeutics for DMD. These experimental efforts will be coupled with additional skill development
activities to produce an integrated training experience to allow my continued development toward a career as
an independent investigator in the neuromuscular disease field.

## Key facts

- **NIH application ID:** 10388754
- **Project number:** 1F31AR080555-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Miguel Aaron Lopez Perez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,552
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388754

## Citation

> US National Institutes of Health, RePORTER application 10388754, Improving cell membrane repair to treat muscular dystrophy (1F31AR080555-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10388754. Licensed CC0.

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