# Altered nucleus-cytoskeleton coupling in dystrophic muscle

> **NIH NIH K01** · MARYMOUNT UNIVERSITY · 2022 · $64,796

## Abstract

Project Summary:
 
Duchenne muscular dystrophy (DMD), the most common and severe form of muscular dystrophy, is
characterized by progressive wasting of skeletal muscles and marked susceptibility to damage. Several
associated processes could underlie the pathology. The nucleus, a regulator of gene expression and a
mechanotransduction hub, has increased movement in mdx (murine model of DMD) muscle. Microtubules
(MTs) serve as the “railroad tracks” for cellular organelle transport, including the nucleus. The nucleus is
connected to MTs and the rest of the cytoskeleton through the LINC (linkers of nucleus and cytoskeleton)
complex. Both, MT organization and LINC complex expression are altered in dystrophic muscle. I will test the
hypothesis that nuclear instability, due to disease-driven MT network and LINC complex alterations, results in
improper myonuclear domain maintenance (with hypermobile and improperly positioned nuclei), and impaired
nuclear mechanotransduction, further driving muscle weakness and susceptibility to injury in dystrophic
muscle. In WT and mdx muscle I will measure:
 1) nuclear spatial distribution & nuclear movement using time-lapse microscopy
 2) myonuclear domain maintenance by measuring RNA spatial distribution of cargoed proteins using
fluorescence in-situ hybridization; and nuclear movement & global transcriptional activity following gaps in
myonuclear domain using laser ablation
 3) nuclear localization of Yes- associated protein (a nuclear relay of mechanical signaling), ERK 1/2 (a key
marker of muscle growth) and FRET based nuclear strain sensors, as end points of nuclear
mechanotransduction, following passive stretch, isometric and eccentric contractions
 4) myonuclear domain maintenance and nuclear mechanotransduction, following blockage of stretch
activated channels to block sarcolemmal signaling pathways
 5) the above parameters using established genetic/pharmacologic manipulations to the MT network & the
LINC complex, and following mini- and micro-dystrophins that have previously shown to either fully or partially
rescue MT network and susceptibility to injury
 Successful completion of this proposal will allow for the development of new avenues to improve
musculoskeletal health for patients with DMD, and potentially other dystrophies. This proposal takes place in a
multi-disciplinary environment at University of Maryland School of Medicine, with support from experts in
physical therapy, physiology, molecular biology, biochemistry, and engineering, such that I can gain skills in
cellular and muscle mechanics to move towards an independent, tenure-track research faculty position.

## Key facts

- **NIH application ID:** 10696635
- **Project number:** 7K01AR074048-05
- **Recipient organization:** MARYMOUNT UNIVERSITY
- **Principal Investigator:** Shama Rajan Iyer
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $64,796
- **Award type:** 7
- **Project period:** 2023-01-20 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10696635

## Citation

> US National Institutes of Health, RePORTER application 10696635, Altered nucleus-cytoskeleton coupling in dystrophic muscle (7K01AR074048-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10696635. Licensed CC0.

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