SLC38A1 protects against aging-related oxidative stress and lipid peroxidation in C2C12 myoblasts: Implication of a ferroptosis-related regulator for skeletal muscle aging

Ferroptosis has been implicated in skeletal muscle aging. Nevertheless, specific ferroptosis-related genes (FRGs) governing skeletal muscle aging remain unclear. The aim of this study was to identify ferroptosis-related marker genes associated with skeletal muscle aging, uncovering potential therapeutic targets for skeletal muscle aging. Data from GSE38718 was utilized to identify differentially expressed FRGs (DE-FRGs) in aging versus normal human skeletal muscle by the least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) algorithms. Validation was conducted using RT-qPCR and Western blot in aging mouse muscle and D-galactose (D-gal)-treated C2C12 cells. SLC38A1 was identified as a significantly downregulated marker for aging skeletal muscle. Overexpression of SLC38A1 mitigated cellular aging in D-gal treated C2C12 cells. In both D-gal treated and sh-SLC38A1 C2C12 cells, increased ROS levels, elevated mtROS, higher intracellular iron concentrations, and intensified lipid peroxidation were observed. In contrast, SLC38A1 overexpression markedly reduced the accumulation of ROS, mtROS, iron concentration, and lipid peroxidation associated with D-gal treatment in these cells. In conclusion, through screening analyses and validation experiments, we identified SLC38A1 as a ferroptosis-related regulator for skeletal muscle aging.