Muscle iron overload contributes to cancer cachexia-induced muscle wasting

Cancer cachexia is a prevalent and often fatal systemic metabolic condition that is characterized by muscle wasting with or without fat wasting. Muscle wasting is therefore the central component of cancer cachexia but the mechanisms whereby cancer leads to skeletal muscle wasting are not well understood. We used several different mouse models of pancreatic ductal adenocarcinoma (PDAC) as well as C26 allograft, one of the most commonly studied models of cancer cachexia, to study the mechanisms underlying cancer cachexia-induced muscle wasting. Transcriptome analyses on cachexic muscle revealed the upregulation of genes related to iron metabolism. To interrogate whether perturbations to muscle iron metabolism can contribute to muscle wasting, we identified that muscle iron levels are elevated in cachexic muscle. Secondly, mice fed low, medium, and high iron diets and showed a positive correlation between dietary iron intake and the severity of muscle wasting. We further demonstrated that increased muscle iron contributes to muscle wasting by generating muscle-specific transgenic mice overexpressing the transferrin receptor (TFRC), which is the primary method of iron intake into the cell. TFRC transgenic mice exhibited decreased muscle mass and myofiber areas compared to mice not overexpressing TFRC. TFRC transgenic mice injected with C26 cancer cells also showed increased muscle wasting compared to control mice with C26 cells. Furthermore, muscle-specific deletion of TFRC in muscle using a muscle-specific tamoxifen-inducible Cre mouse line bred to a conditional TFRC floxed mouse line rescued C26-induced muscle wasting. Our work rigorously demonstrates that elevated muscle iron leads to muscle wasting, and this elevated muscle iron in cancer cachexic muscle contributes to cancer cachexia-induced muscle wasting. Current work is being done to test whether elevated muscle iron is seen in human samples and to decipher the mechanisms by which muscle iron overload leads to muscle wasting.