# Deciphering the Role of Ferroptosis in the Pathogenesis of Peripheral Artery Disease Myopathy

## TL;DR

This study explores how a type of cell death called ferroptosis contributes to muscle disease in peripheral artery disease patients.

## Contribution

The study identifies ferroptosis as a novel mechanism in peripheral artery disease myopathy and suggests it as a potential therapeutic target.

## Key findings

- Ferroptosis markers like lipid peroxidation and PTGS2 were upregulated in CLI PAD patients.
- Genes related to iron metabolism and autophagy were elevated in PAD muscle tissue.
- Ferroptosis is proposed as a new therapeutic avenue for PAD research.

## Abstract

This study investigates the role of ferroptosis in peripheral artery disease-driven myopathy. Ferroptosis is a form of cell death characterized by iron-dependent lipid peroxidation. In this study, we tested leg muscle tissue from peripheral artery disease patients for different ferroptosis markers to determine whether ferroptosis plays a role in this myopathy. General markers of ferroptosis—such as lipid peroxidation—were increased in the muscle tissue of advanced peripheral artery disease patients. Specific markers related to iron metabolism and autophagy were also elevated. Based on these findings, we conclude that ferroptosis is a component of peripheral artery disease myopathy, and that ferroptosis is a promising new therapeutic avenue for peripheral artery disease research.

This study investigates ferroptosis in the context of peripheral artery disease (PAD), a vascular disease characterized by atherosclerosis of the lower extremities. Muscle atrophy and increased oxidative stress are hallmarks of PAD and correlate with worse clinical outcomes. Given ferroptosis’ association with oxidative stress, we explored its role in PAD myopathy by examining gene and protein markers related to metabolic pathways implicated in ferroptosis using both human PAD patients and cultured myotubes. Intermittent claudication (IC) PAD patients, critical limb ischemia (CLI) PAD patients, and non-PAD controls were recruited for this study. Calf muscle biopsies were analyzed for gene expression using qPCR, and protein levels were determined by Western blotting. Cultured myotubes treated with the ferroptosis inducer erastin provided an in vitro comparison. Results demonstrated upregulation of ferroptosis markers such as lipid peroxidation and PTGS2 gene expression in the muscle of CLI PAD patients compared to controls. Increased expression of ferroptosis-related genes HMOX1, ACSL4, ELAVL1, and Beclin-1 was also observed. Protein analysis showed trends consistent with gene expression in some ferroptosis markers. The increase in ferroptosis markers in CLI PAD patients, particularly in iron metabolism and autophagy pathways, suggests ferroptosis contributes to PAD myopathy.