LCN2-ACOD1 Signalling Affects the Post-Injury Regeneration of Skeletal Muscle Through Mediating Ferroptosis

The normal growth and development of skeletal muscle are crucial for the proper function of organisms. During myoblast development, cell death is a fundamental physiological process, and skeletal muscle damage involves various types of cell death, including Ferroptosis. However, ferroptosis-related biomarkers in skeletal muscle damage remain unclear. This study aimed to investigate the mechanisms by which lipocalin-2 (LCN2), a key protein of iron metabolism, regulates skeletal muscle regeneration post damage by mediating Ferroptosis. When the gastrocnemius muscle (GAS) of mice is acutely injured, LCN2 is significantly upregulated early in the injury. In vitro, LCN2 participates in the inhibition of proliferation and differentiation of C2C12 cells via erastin-induced Ferroptosis. Transcriptomic analysis after the overexpression of LCN2 revealed that the one with the most significant difference among all of the differentially expressed genes (DEGs) was aconitate decarboxylase 1 (Acod1). The inhibition of myogenic factors' expression by LCN2 was associated with the activation of the Ferroptosis signalling pathway, partly attributed to the mitochondrial dysfunction. The ACOD1 inhibitor attenuated mitochondria-associated Ferroptosis induced by LCN2 and alleviated the inhibitory effect of LCN2 on cell viability. These findings highlight the therapeutic potential of targeting the LCN2-ACOD1 signalling to promote myogenesis, providing promising strategies for facilitating the regeneration of skeletal muscle after injury and the treatment of muscle-related diseases.

ACOD1; LCN2; ferroptosis; mitochondria; skeletal muscle regeneration.