# Influence of NOX4 activity on muscle fibrosis after spinal cord injury > **NIH VA I21** · VETERANS HEALTH ADMINISTRATION · 2024 · — ## Abstract Skeletal muscle fibrosis is a pathologic consequence of spinal cord injury (SCI) for which no effective treatment options exist. SCI-induced muscle fibrosis hinders physical rehabilitation efforts by worsening muscle force production, impairing muscle regeneration, and promoting contractures, which contributes to limb impairment caused by SCI. The lack of treatments to counter muscle fibrosis after SCI is largely due to a major knowledge gap in understanding the cellular and molecular pathway(s) underlying its development. Nicotinamide adenine dinucleotide phosphatase [NAD(P)H] oxidase 4 (NOX4) is a reactive oxygen species (ROS) generating enzyme that is an anti-fibrotic target in several tissues, including heart, kidney, liver, lungs. Recently, Hammers (Co-I) identified NOX4 as a driver of muscle fibrosis associated with muscular dystrophy and utilized genetic NOX4 inhibition (NOX4i) and pharmacologic NOX4i (via GKT831) to substantially reduce myofibroblasts in dystrophic muscle and to effectively reverse muscle fibrosis and improve muscle function. The goal of this proposal is to investigate the therapeutic potential of NOX4i in SCI-induced muscle fibrosis. We have established a rat SCI model that exhibits permanent hindlimb impairment and reproduces the skeletal muscle phenotype of persons with severe SCI on a timescale that facilitates ‘high-throughput’ testing of potential interventions. As evidence, muscle fibrosis and atrophy develop over many months in persons with SCI, while our SCI model exhibits peak fibrosis and atrophy rates within 1-2 wks. A causative role of NOX4 in promoting SCI-induced muscle fibrosis has yet to be explored. Although, compelling preliminary data indicate that 1) expression of the Nox4 and other genes associated with fibroblast activity, ECM deposition, and collagen crosslinking are significantly elevated in muscle during the rapid fibrogenic stage in SCI-affected muscle (RNA- seq data from Co-Is Barton & Yarrow) and 2) NOX4 protein is persistently localized to fibrotic areas in muscle after SCI. These data support the central premise of this proposal: heightened NOX4 promotes SCI-induced muscle fibrosis. For this project, rats will undergo Sham surgery vs severe SCI. SCI rats will receive vehicle vs GKT831, a small molecule NOX1/4 inhibitor, using immediate and delayed treatment strategies to discern preventative vs restorative efficacy. Studies will: 1a) identify the GKT831 dose that best attenuates NOX4 activity and fibrosis, 1b) assess the degree to which NOX4 activity and muscle fibrosis change after discontinuing GKT831, and 1c) determine the magnitude of fibrosis reversal and muscle recovery when GKT831 is delayed until fibrosis is established. Rehabilitation-centric outcomes and mechanistic outcomes will be assessed to maximize the potential for future translation and to advance the understanding of SCI-induced muscle fibrosis. This approach is innovative because it targets NOX4, which is upregulated after... ## Key facts - **NIH application ID:** 10807522 - **Project number:** 1I21RX004903-01 - **Recipient organization:** VETERANS HEALTH ADMINISTRATION - **Principal Investigator:** Dana M Otzel - **Activity code:** I21 (R01, R21, SBIR, etc.) - **Funding institute:** VA - **Fiscal year:** 2024 - **Award amount:** — - **Award type:** 1 - **Project period:** 2024-01-01 → 2025-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10807522 ## Citation > US National Institutes of Health, RePORTER application 10807522, Influence of NOX4 activity on muscle fibrosis after spinal cord injury (1I21RX004903-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10807522. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*