# Mechanisms of resealing and rebuilding in muscle repair

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $388,000

## Abstract

Muscle repair is essential to maintain normal muscle function. Muscle injury, whether due to trauma or
overuse, is associated with a loss of muscle membrane integrity. Resealing the disrupted sarcolemma is a
critical step needed for muscle repair. Subtypes of muscular dystrophy arise from genetic mutations that
weaken the sarcolemma, rendering it prone to disruption and requiring robust repair mechanisms. Other
subtypes of muscular dystrophy arise from genetically-driven deficits in repair proteins, and these genetic
disorders have illustrated proteins and mechanisms that contribute to membrane stability and membrane
repair. Studies of injured muscle and dystrophic muscle have uncovered phases of muscle repair, an
immediate resealing phase followed by a rebuilding phase. Sarcolemmal resealing occurs through the
formation of a cap at the site of muscle membrane disruption. We and others have shown that this cap is
enriched for annexin proteins, especially annexin A6, a modifier of muscular dystrophy. Dominant negative
annexin A6 disrupts the formation of the repair cap, through its effects on annexin assembly, leading to
excessive membrane leak and ineffective repair. The repair cap is supported by a ring of “shoulder” proteins
that serve to reinforce the resealing process, and these proteins include dysferlin, MG53, and EHD proteins.
Within the muscle cytoplasm immediately abutting sarcolemmal disruption is an active area that is enriched for
actin and the dysferlin related protein, Fer1L5. Moreover, actin polymerization is required for normal resealing.
Recent work highlighted the role of muscle rebuilding, which follows sarcolemma resealing and includes
sarcomere assembly. Through this research program, we previously demonstrated the role of ferlin proteins
and annexins in sarcolemmal resealing by optimizing high-resolution real-time visualization. We also
developed novel genetic tools to elucidate the interaction of these proteins in membrane events. We now
propose to investigate the role of resealing proteins in their interaction with the actin-rich region in Aim 1. In
Aim 2, we will examine the molecular and temporal overlap of resealing and rebuilding during muscle repair. In
Aim 3, we will use biologically active decellularized matrices to define and probe the role of extracellular
annexins in regulating cellular contributions to muscle repair in health and disease. The outcomes of this work
will discover new protein-cellular interactions to guide the pharmacology of promoting muscle repair.

## Key facts

- **NIH application ID:** 10898009
- **Project number:** 5R01NS047726-19
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** ALEXIS R. DEMONBREUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,000
- **Award type:** 5
- **Project period:** 2003-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898009

## Citation

> US National Institutes of Health, RePORTER application 10898009, Mechanisms of resealing and rebuilding in muscle repair (5R01NS047726-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10898009. Licensed CC0.

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