# Understanding the Transcriptional Networks and Physiologic Adaptations Governing the Clinical Manifestations of Duchenne Muscular Dystrophy

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2022 · $50,482

## Abstract

PROJECT SUMMARY
Duchenne muscular dystrophy (DMD) is a universally fatal disease. DMD patients do not express dystrophin
protein and develop skeletal muscle (SkM) degeneration by age 3-5 with later degeneration in cardiac muscle
(CM) by mid-teens. These patients ultimately succumb to respiratory or cardiac failure by age 25-30. The
underlying mechanisms that regulate DMD progression are not well understood. Using patient-derived induced
pluripotent stem cells (iPSCs) with a spectrum of mutations and disease severity, we can study the mechanisms
governing the clinical manifestations of DMD in SkM and CM. Our preliminary data show that DMD patient iPSC-
CMs have weaker action potentials and longer field potential duration when compared to control lines. Based on
these preliminary results and animal model studies, I hypothesize that loss of dystrophin results in dynamic gene
network changes that cause impaired responses to stress stemming from improper development and
maintenance of striated muscle’s physiologic functions. I will test this central hypothesis in two specific aims. In
Aim 1, I will identify the transcriptional profile and downstream electrophysiological and mechanical adaptations
of striated muscle in response to stress in a panel of DMD patient-derived iPSC lines. My working hypothesis is
that increasing demand for cell contraction leads to similar compensatory mechanisms in patient-derived iPSC-
SkM and -CMs, but the response is more protective in CMs due to their constant recruitment when compared to
unaffected controls. Here, I will employ electrical- and pharmacological approaches to induce contractions and
analyze the effects via RNA sequencing (bulk and single-cell), electrophysiologic measurements (microelectrode
array and whole-cell patch clamp), and membrane permeability assays. Our preliminary studies reveal that, at
baseline, DMD iPSC-SkM and -CMs show a leakier plasma membrane when compared to control lines. In Aim
2, I will characterize dose effects of dystrophin on gene networks that regulate the development and maintenance
of physiologic muscle function. My working hypothesis is that dystrophin depletion during differentiation of human
iPSC-SkM and -CMs results in reversible transcriptional and physiologic changes. Using an inducible and
reversible degradation system in unaffected human iPSCs, we can chemically modulate dystrophin protein levels
during muscle differentiation and, identify the transcriptional profiles and cellular adaptations in response to
varying levels of dystrophin. Collectively, these studies are significant in that they will shed light on transcriptional
network changes due to loss of dystrophin in striated muscle that underlie varying clinical phenotype and onset.
Further understanding of DMD pathophysiology and its progression may offer new therapeutic targets for
muscular dystrophies as well as advance our understanding of normal muscle cell biology and function. The
proposed research and train...

## Key facts

- **NIH application ID:** 10460372
- **Project number:** 5F30HL151138-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Bayardo Isidore Garay
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $50,482
- **Award type:** 5
- **Project period:** 2020-07-27 → 2024-07-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460372

## Citation

> US National Institutes of Health, RePORTER application 10460372, Understanding the Transcriptional Networks and Physiologic Adaptations Governing the Clinical Manifestations of Duchenne Muscular Dystrophy (5F30HL151138-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10460372. Licensed CC0.

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