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

Background 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 muscle 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 Due to metabolic differences, obesity-induced ferroptosis in skeletal muscle and the regulation by DR+Ex exhibiting fiber type-specificity. Specifically, red and white muscle respond to obesity-induced ferroptosis through different pathways; red muscle can inhibit obesity-induced ferroptosis through DR+Ex by GPX4. This deepens the understanding of mechanisms related to skeletal muscle cell death and provides scientific data support for the personalized treatment of related diseases.