# Targeting Nitrate-Nitrite-NO pathway for Ameliorating Muscle and Bone Comorbidities in Duchenne Muscular Dystrophy

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $336,258

## Abstract

Abstract:
Duchenne Muscular Dystrophy (DMD) is a severe, progressive muscular disease that affects
both muscle and bone. To date, effective therapies for DMD are limited. Studies have shown
that reduced nitric oxide (NO) bioavailability resulted from secondary loss of neuronal nitric
oxide synthase (nNOS) in the absence of dystrophin is a key contributor to disease progression.
Restoring NO homeostasis via dietary nitrite and nitrate representing a novel therapeutic
approach due to its ability to be converted to NO in low oxygen and ischemic states that can
bypass nNOS. The purpose of this study is to test the efficacy of inorganic nitrite and explore its
mechanism of action on both skeletal muscle and bone. Our preliminary data, based on a
severe dystrophic mouse model (dKO-dystrophin/utrophin double knock out), demonstrated
disrupted NO homeostasis in dystrophic muscle and more excitingly, oral administration of
nitrite significantly improved the life span and a series of pathological changes in dystrophic
mice, both in skeletal muscle and bone tissues. The mechanisms underlying these
improvements deserve further investigation to provide important preclinical and mechanistic
information for identifying novel therapeutic targets. We hypothesize that inorganic nitrite
administration improves both muscle and bone pathologies in DMD by enhancing NO signaling
pathways in dystrophic muscle and by modulating the expression and secretion of bone-
regulating myokines. We will test this hypothesis in three specific aims. Aim 1: To test the
hypothesis that inorganic nitrite restores nitrate/nitrite pool in dystrophic mice and improves
muscle/bone pathologies and preserves muscle function. Aim 2: To test the hypothesis that
nitrite affects skeletal muscle via myoglobin-mediated NO-cGMP signaling pathway. Aim 3: To
test the hypothesis that in addition to increased mechanical loading, nitrite affects bone
homeostasis via modulating the expression and secretion of bone-regulating myokines from
dystrophic muscle. We anticipate that these findings will provide a novel, safe and low-cost
therapeutic approach benefiting both muscle and bone for the currently untreatable DMD.
Completion of these aims will advance our knowledge of novel mechanisms for the
pathogenesis of bone abnormalities in DMD through bone-regulating myokines as well; which
may uncover new potential therapeutic targets. Importantly, our findings may have profound
translational implications not only to DMD but also to other neuromuscular diseases that lack
normal NO signaling pathway function.

## Key facts

- **NIH application ID:** 10477446
- **Project number:** 5R01AR076357-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Hongshuai Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,258
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477446

## Citation

> US National Institutes of Health, RePORTER application 10477446, Targeting Nitrate-Nitrite-NO pathway for Ameliorating Muscle and Bone Comorbidities in Duchenne Muscular Dystrophy (5R01AR076357-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477446. Licensed CC0.

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