Loss of frataxin leads to iron deficiency in the skeletal muscle by decreased iron uptake

Frataxin (FXN) is essential for mitochondrial function by supporting iron-sulfur cluster biogenesis and heme regulation. Although frataxin deficiency (i.e., Friedreich’s ataxia) is known to cause mitochondrial dysfunction in the brain and heart, likely due to iron overload, its impact on iron metabolism in skeletal muscle remains unclear. Given that iron homeostasis is closely linked to the mechanistic target of rapamycin (mTOR) by regulating iron uptake in various tissues including skeletal muscle, we hypothesized that loss of frataxin would cause iron overload in skeletal muscle via enhanced mTOR-mediated iron uptake and muscle weakness. Using a muscle creatine kinase-driven FXN knockout mouse model (MCK-FXN; Jackson Laboratory #029720; male, 9-10 weeks old), we first characterized the muscle phenotype. In MCK-FXN mice, the ratio of tibialis anterior (TA) muscle mass to femur length was significantly decreased compared to sex- and age-matched control (CON; C57BL/6J) mice (p< 0.05), indicating muscle atrophy. Contrary to our hypothesis, non-heme iron levels were significantly decreased in the TA muscle of MCK-FXN mice (p< 0.05), which was accompanied by decreased expression of iron uptake protein transferrin receptor 1 (TfR1; p< 0.05) as well as reduced mTOR phosphorylation. In addition, we found that tristetraprolin (TTP), a negative post-transcriptional regulator of TfR1, was markedly upregulated under muscle FXN deletion (p< 0.05). Collectively, these findings suggest that diminished mTOR signaling may contribute to muscle iron deficiency by limiting iron uptake, which, in turn, could exacerbate muscle atrophy in the context of frataxin deficiency. Future studies are warranted to determine the broader roles of frataxin in muscle physiology and pathophysiology, with a focus on iron metabolism. Funding sources: This study is supported in part by DOD (HT9425-24-1-00009) and UML seed grant. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.