关键词: 年龄相关肌少症, 铁死亡, 溶质载体家族40成员A, 氧化应激

Abstract: Objective To systematically explore the key genes related to ferroptosis and their potential mechanisms in age-related sarcopenia through gene expression data analysis and animal model experiments. Methods The skeletal muscle gene expression data of age-related sarcopenia mice and healthy control mice were collected from public databases GSE226117 and GSE175562. Through differential expression analysis and weighted gene co-expression network analysis (WGCNA), key genes related to sarcopenia were screened, and their relationship with ferroptosis was further explored by functional enrichment analysis. An aged sarcopenia mouse model was established, and young mice were used as the control. Skeletal muscle tissues and serum samples were collected. HE staining was used to observe the histopathological changes, and immunohistochemistry was employed to detect the expression of the key gene Slc4a1. The levels of GSH, MDA and ROS were detected by ELISA. The expression levels of Slc4a1, Fth1, Gpx4, Slc7a11 and Tfrc were detected by RT-qPCR and Western blot. Results Differential expression analysis identified a total of 1 326 differentially expressed genes in the GSE226117 and GSE175562 datasets, and these genes were clustered into 5 co-expression modules through WGCNA. Among them, the brown module had the highest correlation with age(P＜0.05). Enrichment analysis revealed that Slc4a1, Slc39a8 and Tfrc in the brown module were significantly involved in the regulation of ferroptosis. Slc4a1 was significantly downregulated in both datasets and was further identified as a key gene for sarcopenia(P＜0.05). Compared with the young control group, in the aged sarcopenia mouse model, HE staining showed that the skeletal muscle tissue structure was sparse, and the expression of Slc4a1 was significantly decreased. The level of the antioxidant marker GSH was significantly reduced, while the levels of the lipid peroxidation product MDA and the oxidative stress marker ROS were significantly increased (P＜0.05). The expressions of ferroptosis-related genes including Slc4a1, Fth1, Gpx4, Slc7a11 and Tfrc were all significantly downregulated (P＜0.05). Conclusions Slc4a1 may play a role in the pathological mechanism of sarcopenia by participating in the regulation of ferroptosis, providing a potential target for the diagnosis and treatment of sarcopenia.

Key words: age-related sarcopenia, ferroptosis, solute carrier family 40 member a1, oxidative stress