Mechanism of ferroptosis in progressive injury of skeletal muscle caused by high-voltage electrical burns and the intervention effect of uAMC3203.

BACKGROUND

The mechanism underlying progressive skeletal muscle injury following high-voltage electrical burns (HVEB) remains unclear. Therefore, clarifying this mechanism is essential for developing targeted treatment.

METHODS

Differentially expressed genes (DEGs) between the healthy rats and those with severe muscle contusion were identified using the GSE162565 dataset. Differentially expressed ferroptosis-related genes (DE-FRGs) were extracted, and core genes were screened through bioinformatics analyses. A rat model of HVEB-induced skeletal muscle injury was established, including solvent and ferroptosis-inhibitor (uAMC3202) intervention groups. Skeletal muscle tissues were analyzed for biochemical, functional, histological, transcriptional, and protein-level modifications.

RESULTS

In the severe skeletal muscle contusion model, DEGs at each time point were enriched in the ferroptosis pathway, and five core genes were identified. Macroscopic wound evaluation, functional exercise assessment, histological analysis, and serum creatine kinase measurements confirmed that HVEB induced progressive skeletal muscle damage. At selected post-injury time points, the HVEB group exhibited significantly higher expression levels of Hmox1, Timp1, and Hif1a than those in the control group. Additionally, the expression levels of proteins associated with iron and lipid metabolism increased at specific time points after HVEB. Administration of the ferroptosis inhibitor uAMC3203, markedly attenuated the elevated expressions of Hmox1 and iron metabolism-related proteins in the HVEB injury group at one week.

CONCLUSION

In a rat model of HVEB-induced skeletal muscle injury, Hmox1, Timp1, and Hif1a were upregulated during injury progression. Moreover, uAMC3203 mitigated Hmox1 overexpression and iron metabolism activation in damaged skeletal muscles during the first week following HVEB.