Research conducted by scientists at Kumamoto University has demonstrated that by modulating iron metabolism, it’s possible to significantly slow down muscle deterioration associated with facioscapulohumeral muscular dystrophy (FSHD), a condition for which no effective treatment currently exists. This study has been published in the JCI journal.
FSHD is characterized by its progressive nature, starting with muscle weakness in the face and shoulder area, which subsequently spreads to the limbs. The underlying cause is believed to be the aberrant activation of the DUX4 gene within skeletal muscles. This activation triggers a sequence of pathological events, including oxidative stress, inflammation, and the demise of muscle cells. DUX4 has long been considered a primary therapeutic target, yet the precise mechanisms driving muscle damage remained incompletely understood.
In this new investigation, the researchers focused their attention on iron metabolism, which remains a crucial element influencing the level of intracellular oxidative stress. Utilizing a genetically engineered mouse model of FSHD with controlled DUX4 expression, the investigators ascertained that this factor disrupts the intracellular equilibrium of iron. Consequently, excess iron accumulates in the muscle tissue, initiating ferroptosis—a specific form of cell death linked to lipid peroxidation.
Surprisingly, it was discovered that providing supplementary iron, either through diet or as an intravenous preparation of ferric carboxymaltose, did not exacerbate but rather mitigated the pathological buildup of iron in the muscles. Treated animals displayed improvements in both the structure and function of their muscle tissue: grip strength increased, muscular endurance was enhanced, and treadmill running performance improved.
This beneficial therapeutic outcome was achieved without suppressing the DUX4 gene itself. This suggests the effect operates “downstream of the cascade”—at the level of metabolic and cellular dysfunctions. Gene activity analysis revealed that restoring normal iron metabolism suppresses inflammatory and lysosomal processes, thereby protecting muscles from degradation.
According to the authors of the study from the Institute of Molecular Embryology and Genetics at Kumamoto University, this work highlights iron metabolism as a previously underestimated yet critically important therapeutic target for FSHD.
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