Elevated labile iron contributes to membrane repair deficits in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by expression of the transcription factor DUX4, which is associated with plasma membrane (PM) repair deficits. Here, we show that PM injury triggers a mild but significant increase in DUX4 mRNA expression in FSHD myoblasts. These cells demonstrate the dysregulation of genes critical for PM repair, which are sensitive and specific for FSHD muscle tissue, and include regulators of ferroptosis. FSHD myoblasts also present with elevated labile ferrous iron and lipid peroxidation-hallmarks of ferroptotic stress. In FSHD muscle biopsies, the expression of ferroptosis biomarkers is elevated, predictive of inflammation. and positively correlated with fatty infiltration. Increasing labile iron and lipid peroxidation worsen PM repair in FSHD myoblasts, while treatment with the iron chelator 2,2'-Bipyridyl and ferroptosis inhibitor ferrostatin-1 improves repair. These data are the first to identify signs of ferroptotic stress in human FSHD myoblasts and demonstrate the potential benefit of targeting ferroptosis in FSHD.