ROLE OF LIPOCALIN 2 AND IRON METABOLISM IN CANCER AND GLUCOCORTICOID-INDUCED SKELETAL MUSCLE ATROPHY

 

Cachexia is a wasting syndrome, marked by severe skeletal muscle atrophy, significantly increases mortality in various diseases including cancer, yet its mechanisms remain poorly understood. We previously identified major alterations of iron metabolism in the skeletal muscle of tumor-bearing mice and in particular a decrease in mitochondrial iron, resulting in mitochondrial dysfunction. However, the underlying causes of these alterations in muscle iron metabolism remain unknown. Lipocalin 2 (LCN2) an iron-sequestering protein, has been identified as one of the most upregulated genes in various models of skeletal muscle atrophy. Therefore, we investigated the role of LCN2 in skeletal muscle atrophy associated with cancer and chronic glucocorticoid treatment.

LCN2 levels surged in muscles of both C26 tumor-bearing mice and dexamethasone treated mice. In vitro, LCN2 overexpression reduced C2C12 myotube diameter, while its silencing protected myotubes from dexamethasone-induced atrophy. In vivo, we found that aminoglutethimide, a drug inhibiting glucocorticoids synthesis, suppressed LCN2 expression in the skeletal muscle of C26 tumor-bearing mice thus suggesting that elevated levels of glucocorticoids are responsible for the upregulation of LCN2 in the C26 model Dexamethasone treatment, in vitro and in vivo, significantly reduced mitochondrial iron levels, mirroring C26 model iron metabolism alterations.

Our finding shed light on cancer and glucocorticoid-induced skeletal muscle wasting mechanisms, highlighting LCN2 as a potential therapeutic target for muscle wasting diseases.