Iron homeostasis disruption and lipid peroxidation in skeletal muscle during short‐term immobilization

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.