Disuse‐induced muscle atrophy may involve dysregulated iron metabolism, yet the underlying mechanisms are unclear. We examined iron homeostasis in mouse gastrocnemius muscle following 14‐day casting‐induced immobilization. Muscle mass declined by ~ 25%, accompanied by increased nonheme iron and ferritin heavy chain levels. Despite iron accumulation, transferrin receptor 1 and iron regulatory protein 2 were paradoxically upregulated, suggesting disruption of IRP/IRE feedback control. Additionally, levels of 4‐hydroxynonenal, a marker of lipid peroxidation, were elevated without compensatory responses from SLC7A11/xCT or GPx4. These findings indicate that short‐term immobilization disrupts iron regulatory mechanisms and induces oxidative stress exceeding antioxidant capacity. Iron dysregulation and lipid peroxidation may contribute to the early pathogenesis of disuse‐induced muscle atrophy and represent potential therapeutic targets.
Yokogawa et al. (Thu,) studied this question.