Characterization of the Role of the Iron Exporter Ferroportin in the skeletal muscle

Iron is a major player in various metabolic processes in organisms and cells, including oxygen transport and energy production. In the last years, cancer cell iron metabolism has been the focus of many studies demonstrating its importance in tumour growth, progression, and therapy. Indeed, recent insights have linked muscle iron metabolism to cancer cachexia, a wasting syndrome characterized by loss in muscle mass. Particularly, iron supplementation has been shown to revert the cachectic phenotype in murine models providing a novel understanding of cancer-induced skeletal muscle wasting. Ferroportin is the only known cellular iron exporter, and its mutations cause systemic dysregulations of iron metabolism due to impaired dietary iron absorption and consequently altered plasma iron levels. In order to assess the impact of muscular iron export in regulating muscle and systemic iron homeostasis, we generated a muscle-specific Ferroportin-knockout (FPN-mKO). This study analyses the effects of FPN-mKO both on muscle biology and tumour growth. We demonstrated that FPN-mKO did not alter mice strength or muscle biology but induced a dysregulation in iron metabolism in muscle cells, determining decreased Transferrin receptor 1 expression, thus controlling proper iron homeostasis. Furthermore, we observed no change in the tumour growth rate between control and KO mice upon the injection of LLC cells; also, even though atrogenes were induced in tumour-bearing mice, no muscle atrophy or cachexia was observed. Interestingly, lung metastases were significantly increased in number and extension in FPN-mKO mice. These findings indicate that FPN-mKO does not sensitize LLC-injected mice to cachexia or muscle atrophy and increases lung metastases; however, it markedly modifies iron metabolism in muscle cells. Thus, further efforts are needed to better characterize this model at a cellular and systemic level.