# Cytoskeletal Interactions of Dystrophin

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $554,761

## Abstract

PROJECT SUMMARY/ABSTRACT
The long-term objective of this project is to fully define the functions of dystrophin in striated muscle to
understand how its absence or abnormality leads to the pathologies observed in Duchenne and Becker
muscular dystrophies, and to inform on the potential for miniaturized dystrophins or utrophin to substitute for
dystrophin in a therapeutic context. In the current project period, we generated a new line of transgenic mdx
mice that expresses dystrophin lacking in vitro microtubule binding activity, but which surprisingly presented
with a fully rescued cortical microtubule lattice. We also analyzed microtubule organization in existing lines of
transgenic mdx mice expressing different truncated dystrophin constructs and found that two different micro-
dystrophins were less effective than two mini-dystrophins in restoring microtubule organization in mdx
muscles. Exciting new preliminary data identified a second region required for microtubule organization and
showed that the microtubule lattice of transgenic mdx mice expressing mini- or micro-dystrophins is rapidly
disrupted by eccentric contraction through a mechanism involving reactive oxygen species. Thus, the first
goal of aim 1 is to generate and characterize two new lines of transgenic mdx mice that will more definitively
confirm the regions of dystrophin necessary for stable microtubule lattice organization. Aim 1 will then
elucidate the relationship between eccentric contraction and reactive oxygen species in disrupting the
microtubule lattice in mdx muscles expressing mini- or micro-dystrophins. Finally, aim 1 will delineate the
interplay between the dystrophin-glycoprotein complex and cytoplasmic actins in effecting stable cortical
microtubule organization in mature skeletal muscle. We have also recently published atomic force microscopy
data suggesting that utrophin may be much stiffer than dystrophin and functionally less equivalent than
previously thought. We have acquired exciting preliminary data showing that the cellular system used to
express a model utrophin fragment significantly impacts its mechanical properties. In aim 2, we will extend our
preliminary studies in bacteria and insect cells to measure the mechanical properties of dystrophin and
utrophin constructs expressed in mammalian myoblasts. We will then carry out the first mechanical
characterization of single, full-length dystrophin molecules for comparison with our published utrophin data.
And finally, in aim 2 we will investigate how internal truncations affect the mechanical behavior of the most
therapeutically-relevant miniaturized dystrophins. Our proposed studies will provide new understanding into
the functions of dystrophin and utrophin in healthy muscle and will inform on the potential for miniaturized
dystrophins and utrophin to functionally replace dystrophin as therapeutic approaches for Duchenne muscular
dystrophy.

## Key facts

- **NIH application ID:** 10897014
- **Project number:** 5R01AR042423-29
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** JAMES M ERVASTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $554,761
- **Award type:** 5
- **Project period:** 1994-07-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897014

## Citation

> US National Institutes of Health, RePORTER application 10897014, Cytoskeletal Interactions of Dystrophin (5R01AR042423-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10897014. Licensed CC0.

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