Regulation of Ferroptosis in Obesity: Muscle Type-Specific Effects of Dietary Restriction and Exercise

Obesity is a significant global health issue and a risk factor for numerous diseases. Ferroptosis, an iron-dependent regulated cell death, is triggered by iron overload and the excessive accumulation of lipid peroxidation mediated by reactive oxygen species. Studies has identified a strong association between ferroptosis and obesity. Additionally, dietary restriction (DR) and DR combined with exercise (DR+Ex) are effective strategies for managing obesity and ferroptosis. However, the regulation of ferroptosis and its signaling pathways in skeletal muscle under conditions of obesity, DR, and DR+Ex remains poorly understood.

Methods

Mice were divided into four groups: normal diet, high-fat diet, high-fat DR, and high-fat DR+Ex. All mice were fed ad libitum with either a normal or high-fat diet for the first 14 weeks, followed by the respective interventions for the subsequent 8 weeks. Mice muscle ferroptosis were examined by immunohistochemistry, Hematoxylin & Eosin, Masson’s trichrome, Prussian blue staining, and Western-Immunoblot.

Results

The high-fat diet resulted in increased inflammatory cell infiltration, fibrosis, and iron accumulation. Red and white muscles showed increased expression of 4-HNE, regulated by GPX4 and NCAO4, respectively. DR and DR+Ex reduced downstream 4-HNE expression by regulating GPX4 in red muscle.

Conclusion

Red and white muscles respond to obesity-induced ferroptosis through different signaling pathways. The regulation of ferroptosis by DR and DR+Ex is muscle type-specific. Specifically, red muscle is more sensitive to the regulation of ferroptosis signaling by DR and DR+Ex compared to white muscle.