Changes in skeletal muscle iron metabolism outpace amyotrophic lateral sclerosis onset in transgenic rats bearing the G93A hmSOD1 gene mutation

• Published in: Free radical research Vol. 48; no. 11; p. 1363
• Main Authors: Halon, M, Kaczor, J J, Ziolkowski, W, Flis, D J, Borkowska, A, Popowska, U, Nyka, W, Wozniak, M, Antosiewicz, J
• Format: Journal Article
• Language: English
• Published: England 01-11-2014
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Apoferritins - metabolism; Cation Transport Proteins - metabolism; Disease Progression; Enzyme-Linked Immunosorbent Assay; Hepcidins - metabolism; Humans; Immunoblotting; Iron - metabolism; Male; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Mutation - genetics; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Shc Signaling Adaptor Proteins - metabolism; Src Homology 2 Domain-Containing, Transforming Protein 1; Superoxide Dismutase - physiology; Superoxide Dismutase-1; iron; oxidative damage; ferritin; amyotrophic lateral sclerosis
• ISSN: 1029-2470
• DOI: 10.3109/10715762.2014.955484

Recently, iron and the adaptor protein "p66Shc" have been shown to play an important role in the development of amyotrophic lateral sclerosis (ALS) in rats. We hypothesized that changes in muscle p66Shc activity and iron metabolism would appear before visible symptoms of the disease occurred.
In the present study, we used transgenic rats bearing the G93A hmSOD1 gene mutation and their non-transgenic littermates to test this hypothesis. We examined muscle p66Shc phosphorylation and iron metabolism in relation to oxidative stress in animals at three disease stages: asymptomatic (ALS I), disease onset (ALS II), and end-stage disease (ALS III).
Significant changes in iron metabolism and markers of lipid and protein oxidation were detected in ALS I animals, which manifested as decreased levels of ferritin H and ferroportin 1 (Fpn1) and increased levels of ferritin L levels. Muscles of ALS I rats possessed increased levels of p66Shc phosphorylated at Ser(36) compared with muscles of control rats. During disease progression, level of ferritin H significantly increased and was accompanied by iron accumulation.
This study showed that multiple mechanisms may underlie iron accumulation in muscles of ALS transgenic rats, which include changes in blood hepcidin and muscle Fpn1 and increased level of muscle ferritin H. These data suggest that impaired iron metabolism is not a result of changes in motor activity.