Increased iron levels and iron-generated reactive oxygen species may play a role in the pathology of Duchenne muscular dystrophy (DMD) models, according to a new study published in the Journal of Cachexia, Sarcopenia, and Muscle.

Muscles exhibiting severe pathology in mouse models of DMD showed increased levels of elemental iron, and increased levels of the iron storage proteins ferritin and ferroportin were also observed compared to control mice (P <.05 for both).

Despite the dyshomeostasis of iron in the muscles of the mouse models, lower expression of the rate-limiting enzyme for heme synthesis, 5-aminolevulinate synthase 1, and the heme-containing protein myoglobin were also observed in dystrophic muscles. To test the effect of elevated or reduced iron levels in the muscle models, researchers decreased iron levels in the mice through chelation with deferiprone or increased levels through the iron-enriched feed.


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Treatment with deferiprone resulted in reduced muscle iron levels, however not at significant levels (-30%; P <0.1). Deferiprone treatment did lead to reduced fibrosis (-26%; P <.05) and reactive oxygen species. The chelation also suppressed mitochondrial activity and the production of heme-containing proteins including myoglobin and cytochrome-C, however.

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No effects on growth, body composition, muscle mass, blood glucose, or maximum grip strength were observed. In contrast, iron supplementation elevated levels of iron in the muscles (+25%; P <.0205) as well as increased ferritin levels by 87% (P <.05). No changes in disease pathology, growth, body composition, muscle mass, blood glucose, or maximum grip strength were observed.

“Iron chelation with deferiprone at one dose ameliorated fibrosis but suppressed mitochondrial function. Conversely, iron feeding elevated iron and heme proteins, but had no impact on fibrosis. Thus, iron status impacts on the pathology of DMD and warrants further elaboration,” the authors summarized.

Two murine models of DMD were utilized during the study, mdx and dko mice. The mdx mice, which have a point mutation leading to a lack of dystrophin, were utilized as they are the most commonly used murine model of DMD with the diaphragm being their most impacted muscle. The dko mouse model lacks both dystrophin and utrophin proteins and these mice have affected hindlimb muscles and represent a more severe disease pathology.

Reference

Alves FM, Kysenius K, Caldow MK, et al. Iron overload and impaired iron handling contribute to the dystrophic pathology in models of Duchenne muscular dystrophy. J Cachexia Sarcopenia Muscle. Published online March 6, 2022. doi:10.1002/jcsm.12950