Iron Supplements Show Promise in Restoring Muscle Strength for Muscular Dystrophy

Researchers at Kumamoto University have demonstrated that iron supplementation can significantly alleviate muscle pathology and functional decline in a mouse model of facioscapulohumeral muscular dystrophy (FSHD), a rare genetic muscle disease for which no effective treatment currently exists. The work is published in the Journal of Clinical Investigation. FSHD is characterized by progressive muscle weakness that typically begins in the face and shoulders and gradually spreads to the upper arms and lower limbs. The disease is caused by aberrant expression of the toxic transcription factor DUX4 in skeletal muscle, which induces oxidative stress, inflammation, and muscle degeneration. Although DUX4 is widely recognized as a central therapeutic target, the molecular processes that translate DUX4 expression into muscle damage remain incompletely understood. In the new study, the research team focused on iron metabolism, a critical regulator of oxidative stress. Using a genetically engineered mouse model that conditionally expresses DUX4 in skeletal muscle, the researchers found that DUX4 disrupted intracellular iron homeostasis, leading to iron accumulation in muscle tissue. This abnormal iron accumulation resulted in oxidative damage and activation of the ferroptosis pathway, which is known as iron-mediated cell death driven by excessive lipid peroxidation. Importantly, iron supplementation—administered through diet as well as via ferric carboxymaltose (FCM), an FDA-approved intravenous iron formulation—significantly reduced pathological iron accumulation in muscle tissue. Treated mice showed marked improvements in muscle structure and function, including increased grip strength, enhanced muscle force generation, and improved treadmill running performance. Notably, these therapeutic effects occurred without reducing DUX4 expression itself, indicating that iron supplementation acts downstream of the disease's primary genetic cause. Transcriptome analyses further revealed that iron supplementation suppressed the abnormal activation of inflammatory and lysosomal pathways induced by DUX4, providing mechanistic insight into how restoring iron balance protects muscle tissue from degeneration. Furthermore, in vitro compound library screening uncovered a drug to attenuate DUX4 toxicity, which was ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis. Treatment with Fer-1 in DUX4-Tg mice successfully improved grip strength and running performance, suggesting that the ferroptosis pathway could be a therapeutic target for FSHD. "Our findings identify iron metabolism as a previously underappreciated therapeutic target in FSHD," said Professor Yusuke Ono of the Institute of Molecular Embryology and Genetics at Kumamoto University. "By correcting iron dysregulation, it may be possible to preserve muscle function even when DUX4 expression cannot be completely suppressed." Although clinical studies will be required to confirm safety and efficacy in patients, this work opens a new avenue for FSHD treatment strategies and underscores the potential of repurposing existing iron formulations for neuromuscular diseases.