2. Academic Validation
  3. Iron supplementation alleviates pathologies in a mouse model of facioscapulohumeral muscular dystrophy

Iron supplementation alleviates pathologies in a mouse model of facioscapulohumeral muscular dystrophy

  • J Clin Invest. 2025 Jul 1;135(17):e181881. doi: 10.1172/JCI181881.
Kodai Nakamura 1,  Huascar Pedro Ortuste Quiroga 1,  Naoki Horii 1,  Shin Fujimaki 1,  Toshiro Moroishi 2 3 4,  Keiichi I Nakayama 5 6,  Shinjiro Hino 7,  Yoshihiko Saito 8,  Ichizo Nishino 8,  Yusuke Ono 1 3 9
Affiliations

Affiliations

  • 1 Department of Muscle Development and Regeneration, Institute of Molecular Embryology and Genetics.
  • 2 Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, and.
  • 3 Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  • 4 Division of Cellular Dynamics, Medical Research Laboratory, and.
  • 5 Anticancer Strategies Laboratory, Advanced Research Initiative, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan.
  • 6 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 7 Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
  • 8 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 9 Muscle Biology Laboratory, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan.
PMID: 40591405 DOI: 10.1172/JCI181881
Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in muscle weakness. However, the mechanism by which DUX4 exerts its toxicity remains unclear. In this study, we observed abnormal iron accumulation in muscles of patients with FSHD and in mice with muscle-specific DUX4 expression (DUX4-Tg mice). Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptake of iron did not improve but rather exacerbated FSHD pathology in DUX4-Tg mice. Unexpectedly, however, iron supplementation, from either a high-iron diet or intravenous iron administration, resulted in remarkable improvement in grip strength and running performance in DUX4-Tg mice. Iron supplementation suppressed abnormal iron accumulation and the ferroptosis-related pathway involving increased lipid peroxidation in DUX4-Tg muscle. Muscle-specific DUX4 expression led to retinal vasculopathy, a part of FSHD pathology, which was prevented by iron administration. Furthermore, high-throughput compound screening of the Ferroptosis pathway identified drug candidates including ferrostatin-1 (Fer-1), a potent inhibitor of lipid peroxidation. Treatment with Fer-1 dramatically improved physical function in DUX4-Tg mice. Our findings demonstrate that DUX4-provoked toxicity is involved in the activation of the ferroptosis-related pathway and that supplementary iron could be a promising and readily available therapeutic option for FSHD.

Keywords

Metabolism; Muscle; Muscle biology; Neuromuscular disease; Skeletal muscle.

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