# Modifying heart and skeletal muscle in muscular dystrophy

> **NIH NIH P50** · UNIVERSITY OF FLORIDA · 2022 · $486,520

## Abstract

ABSTRACT
Project 2 of this Wellstone Center has been studying modifiers of muscular dystrophy and its associated
cardiomyopathy. Through the first funding period of this Wellstone Center (2010-2015), we evaluated latent
TGF-b binding protein 4 (LTBP4) as a modifier of muscular dystrophy, discovering human genetic variation that
correlated with prolonged ambulation in Duchenne Muscular Dystrophy (DMD). The Ltbp4 modifier data from
mice demonstrated that LTBP4’s hinge is critical for stabilizing latent TGFb and myostatin and preventing their
release and activity. From this work, we are advancing anti-LTBP4 antibodies as a potential biological agent to
treat DMD. We identified a second modifier, Anxa6, encoding annexin A6. Using high resolution, real-time
microscopy we found that annexin A6 functions as a mediator of membrane repair. We also uncovered a
critical interaction between glucocorticoid steroids and annexin A6, demonstrating that intermittent low-dose
glucocorticoid steroids promote membrane resealing, in part, by upregulating annexin A6. Glucocorticoid
steroids are a pharmacologic modifier of DMD, but their mechanisms of action in DMD are incompletely
understood. In mouse models of muscular dystrophy, we found that intermittent low dose steroids enhanced
muscle repair and muscle performance without the same adverse side effects elicited from daily steroids.
Furthermore, we found that intermittent steroid use improved strength and function in several mouse models of
Limb Girdle Muscular Dystrophy, prompting a pilot clinical trial in patients with muscular dystrophy types not
normally treated with steroids. We will now focus on defining how steroid use alters muscle inflammatory cells
and how this is reflected in serum and cytokine profiles. These studies are specifically designed to translate
into the human setting. We will also explore a novel compound that leads to CaMK activation, a key feature
seen after intermittent steroid use. We plan to test models for Duchenne Muscular Dystrophy as well as Limb
Girdle Muscular Dystrophy. In the last aim, we will test a putative new modifier for the heart in muscular
dystrophy, as this modifier is expected to promote similar metabolic shifts seen in muscle after intermittent
steroid use. Overall, these experiments are designed to identify dosing strategies, pharmacodynamic
biomarkers, and novel treatments that can be used in muscular dystrophy patients on their own or as adjuncts
to gene therapy. The outcomes from these experiments will be used in translating these findings to patients
with multiple forms of muscular dystrophy. This Project is conducted jointly with investigators from
Northwestern and UCLA with collaboration from investigators and core facilities at the University of Florida.

## Key facts

- **NIH application ID:** 10459583
- **Project number:** 5P50AR052646-17
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** H Lee Sweeney
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $486,520
- **Award type:** 5
- **Project period:** 2005-09-25 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459583

## Citation

> US National Institutes of Health, RePORTER application 10459583, Modifying heart and skeletal muscle in muscular dystrophy (5P50AR052646-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10459583. Licensed CC0.

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