# High mobility group box 1 (HMGB1) is a potential disease biomarker in cell and mouse models of Duchenne muscular dystrophy

## TL;DR

This study identifies HMGB1 as a potential biomarker for inflammation in Duchenne muscular dystrophy using cell and mouse models.

## Contribution

HMGB1 is proposed as a novel biomarker for DMD-related inflammation and treatment response.

## Key findings

- HMGB1 protein levels increased in human iPSC-derived DMD myocytes and decreased with microdystrophin treatment.
- AAV-microdystrophin reduced HMGB1 in B10-mdx mice but not in D2-mdx mice, showing strain-specific differences.
- RNA sequencing identified HMGB1 as a candidate biomarker in mdx mouse models of DMD.

## Abstract

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder affecting 1:3500 male births and is associated with myofiber degeneration, regeneration, and inflammation. Glucocorticoid treatments have been the standard of care due to immunomodulatory/immunosuppressive properties but novel genetic approaches, including exon skipping and gene replacement therapy, are currently being developed. The identification of additional biomarkers to assess DMD-related inflammatory responses and the potential efficacy of these therapeutic approaches are thus of critical importance. The current study uses RNA sequencing of skeletal muscle from two mdx mouse models to identify high mobility group box 1 (HMGB1) as a candidate biomarker potentially contributing to DMD-related inflammation. HMGB1 protein content was increased in a human iPSC-derived skeletal myocyte model of DMD and microdystrophin treatment decreased HMGB1 back to control levels. In vivo, HMGB1 protein levels were increased in vehicle treated B10-mdx skeletal muscle compared to B10-WT and significantly decreased in B10-mdx animals treated with adeno-associated virus (AAV)-microdystrophin. However, HMGB1 protein levels were not increased in D2-mdx skeletal muscle compared to D2-WT, demonstrating a strain-specific difference in DMD-related immunopathology.

Summary: Duchenne muscular dystrophy is a devastating that currently has limited treatment options. RNA sequencing and downstream analysis in iSkM and mdx samples revealed HMGB1 may be a relevant treatment biomarker.