# Targeting EGR1-ATF3 signaling mitigates paravertebral muscle degeneration by regulating cell death and inflammaging

## TL;DR

This study identifies key genes involved in muscle degeneration and inflammation in aging paravertebral muscles, offering potential targets for treatment.

## Contribution

The study identifies the EGR1-ATF3 signaling axis as a novel target for mitigating paravertebral muscle degeneration.

## Key findings

- Silencing ATF3 reduces cell death and inflammation while preserving extracellular matrix integrity.
- EGR1 knockdown protects against muscle degeneration by downregulating ATF3.
- The identified genes show potential as diagnostic biomarkers for paravertebral muscle degeneration.

## Abstract

The paravertebral muscles play a critical role in maintaining dynamic spinal stability and physiological function. With aging, these muscles undergo senescence and degeneration, contributing to spinal instability and the development of low back pain. Age-related cellular death further accelerates chronic, low-grade inflammation termed “inflammaging” and disrupts the extracellular matrix (ECM), representing a key pathogenic mechanism driving paravertebral muscle degeneration (PMD). However, the core regulatory genes orchestrating inflammaging in this context have yet to be fully elucidated. The paravertebral muscles play an important role in supporting dynamic stability and physiological function of the spine. This study identified 409 differentially expressed genes (DEGs) through RNA sequencing. Subsequent bioinformatics analysis revealed 81 functionally relevant DEGs, with several hub genes such as Activating Transcription Factor 3 (ATF3), Cyclin-Dependent Kinase Inhibitor 1 A (CDKN1A/p21), and Interleukin-6 (IL-6) being significantly upregulated. These genes are associated with cellular death, ECM metabolic dysregulation, and inflammaging. Functional experiments demonstrated that silencing ATF3 attenuated cellular death, reduced inflammatory signaling, and preserved ECM integrity by modulating downstream effectors including CDKN1A/p21, IL6, Gasdermin E (GSDME), and Glutathione Peroxidase 4 (GPX4). Further network analysis identified the Early Growth Response 1 (EGR1)–ATF3 signaling axis, with EGR1 knockdown protecting against PMD through downregulation of ATF3. These genes may also exhibit high specificity and sensitivity for distinguishing PMD, suggesting their potential utility as diagnostic biomarkers. Overall, this study provides new insights into the molecular mechanisms underlying PMD and offers promising targets for therapeutic intervention.

The online version contains supplementary material available at 10.1186/s40659-025-00634-1.