# Costamere Defects in Muscular Dystrophies

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $599,579

## Abstract

PROJECT SUMMARY/ABSTRACT
While abundant skeletal (ask-actin) and cardiac (aca-actin) actin isoforms are famous for their essential role in
striated muscle contraction, low abundance non-muscle “cytoplasmic” actin isoforms (bcyto- and gcyto-actin) are
also emerging as important in the maintenance of specialized structures (and functions) in normal and
diseased skeletal muscle. During this project, we generated and characterized muscle-specific mouse lines
either lacking or overexpressing bcyto-actin or gcyto-actin to understand their endogenous functions and role(s) in
dystrophin-deficient muscular dystrophy. Interestingly, each bcyto-actin or gcyto-actin single knockout develops a
qualitatively similar phenotype characterized by a progressive myopathy with significant myofiber
degeneration/regeneration and muscle weakness. We have shown that skeletal muscle-specific
overexpression of bcyto-actin or gcyto-actin in dystrophin-deficient mdx mice affords significant protection from
eccentric contraction-induced force drop while overexpression of a C272A mutant of gcyto-actin affords no
protection. These and other data suggest that eccentric contraction drives a rapidly-reversible, reactive
oxygen species (ROS)-mediated inhibition of sarcomeric contractility that may function to protect dystrophic
muscles from damage caused by repeated, high force contractions. Our new preliminary data show that
muscle-specific ablation of bcyto-actin or gcyto-actin from wildtype muscle results in eccentric contraction-induced
force drop that is reversed by the nonspecific antioxidant N-acetylcysteine. Finally, we have obtained new
data suggesting that gcyto-actin is important for repair of membrane damage. Going forward, we will make use
of our unique animal models, isoform-specific reagents, and biochemical and physiological methodologies to
address new fundamental questions about cytoplasmic actins in normal skeletal muscle function and in
dystrophin-deficient muscular dystrophy. In aim 1, we will identify the sources of ROS contributing to eccentric
contraction-induced force drop in dystrophic mdx skeletal muscle as well as the downstream targets of ROS
that ultimately inhibit force production. In aim 2, we will investigate the role of oxidative stress in driving the
myopathy and eccentric contraction-induced force drop associated with genetic ablation of bcyto- or gcyto-actin in
skeletal muscle. In aim 3, the interplay between cytoplasmic actin isoforms and ROS in membrane repair will
be investigated using state-of-the-art imaging approaches to analyze muscles from the same mouse lines
used in aims 1 and 2. The results of the proposed studies will further delineate the unique and important
contributions of cytoplasmic actin isoforms to the function of normal and dystrophic skeletal muscle.

## Key facts

- **NIH application ID:** 10130211
- **Project number:** 2R01AR049899-17A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** JAMES M ERVASTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,579
- **Award type:** 2
- **Project period:** 2005-02-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130211

## Citation

> US National Institutes of Health, RePORTER application 10130211, Costamere Defects in Muscular Dystrophies (2R01AR049899-17A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10130211. Licensed CC0.

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