# Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $382,607

## Abstract

Summary
Many muscular dystrophies are caused by mutation in proteins that compromise the stability and integrity of
the muscle sarcolemma, which results in high serum level of muscle enzymes such as Creatine Kinase.
Understanding the mechanism by which healthy myofibers maintain their sarcolemmal integrity would enable
development of new therapies for these muscular dystrophies. Miyoshi myopathy (MM) and limb girdle
muscular dystrophy (LGMD) 2B, caused by mutations in dysferlin gene are such diseases. We have identified
that loss of sarcolemmal integrity in LGMD2B muscle fibers is due to the delay in fusion of lysosome with the
injured sarcolemma. This causes a delay in injury-triggered secretion of the lysosomal enzyme acid
sphingomyelinase. Providing extracellular sphingomyelinase reverses the repair deficit and offers a potential
therapy for LGMD2B. However, the mechanism by which alteration in sphingomyelin and other cell membrane
lipids facilitates repair of injured muscle cell membranes has not been fully elucidated. This proposal aims to
identify how lipids and lipid modifying enzymes such as acid sphingomyelinase facilitate maintenance of
sarcolemmal integrity and facilitate repair of injured sarcolemma. We will achieve this by visualizing and
modifying lipid composition of healthy muscle cell membrane and assess their effect on sarcolemmal integirty.
We will also assess how lipids respond are altered in the LGMD2B patient and mouse muscle cells to identify
potential therapeutic interventions to address these alterations. One such intervention we have established is
the use of acid sphingomyelinase and we will evaluate its preclinical therapeutic potential for LGMD2B. These
studies will not only help understand the role of lipids in maintenance of sarcolemmal integrity, but also provide
insight into developing novel therapies for muscular dystrophies that move beyond targeting the proteins to
also targeting the sarcolemmal lipids.

## Key facts

- **NIH application ID:** 9965641
- **Project number:** 5R01AR055686-10
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Jyoti K Jaiswal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,607
- **Award type:** 5
- **Project period:** 2008-07-02 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965641

## Citation

> US National Institutes of Health, RePORTER application 9965641, Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy (5R01AR055686-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9965641. Licensed CC0.

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