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

Halon, Malgorzata; Kaczor, Jan Jacek; Ziółkowski, Wiesław; Flis, Damian Józef; Borkowska, Andzelika; Popowska, Urszula; Nyka, Walenty M.; Woźniak, Michał; Antosiewicz, Jędrzej

doi:10.3109/10715762.2014.955484

Cited by 22 publications

(31 citation statements)

References 36 publications

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“…The activity of catalase was higher in TA from ALS II and ALS III muscles ( Figure C). We have shown previously that progression of the disease was accompanied by no change in soleus (SOL) muscle mass and some decrease in TA . In the present study, we confirmed this observation based on EDL muscle, which is mostly built of white fibres and that is where a significant decrease of its mass was observed in ALS II and ALS III animals ( Figure D).…”

Section: Resultssupporting

confidence: 91%

“…The mechanism of iron transport into a cell is quite well understood; however, the cause of iron accumulation, which is observed in certain tissues, is not known. Most of the cells are able to export iron by ferroportin, and we observed that the level of ferroportin protein significantly decreased during progression of ALS in rats . It is important to note that tissue iron accumulation is associated with several morbidities; however, it is still not clear if the phenomenon is a cause or effect of the disease process .…”

Section: Introductionmentioning

confidence: 74%

“…The role of iron is supported by the effects of iron chelator, which has been shown to extend the life span of transgenic animals by 5 weeks . In addition, iron accumulation in the central nervous system of ALS patients as well as in the skeletal muscle of transgenic animals have been reported . Iron is a transition metal participating in redox reactions.…”

Section: Introductionmentioning

confidence: 99%

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hmSOD1 gene mutation‐induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway

Halon-Golabek

Borkowska

Kaczor

et al. 2018

J cachexia sarcopenia muscle

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BackgroundRecently, skeletal muscle atrophy, impairment of iron metabolism, and insulin signalling have been reported in rats suffering from amyotrophic lateral sclerosis (ALS). However, the interrelationship between these changes has not been studied. We hypothesize that an impaired Akt–FOXO3a signalling pathway triggers changes in the iron metabolism in the muscles of transgenic animals.MethodsIn the present study, we used transgenic rats bearing the G93A hmSOD1 gene and their non‐transgenic littermates. The study was performed on the muscles taken from animals at three different stages of the disease: asymptomatic (ALS I), the onset of the disease (ALS II), and the terminal stage of the disease (ALS III). In order to study the molecular mechanism of changes in iron metabolism, we used SH‐SY5Y and C2C12 cell lines stably transfected with pcDNA3.1, SOD1 WT and SOD1 G93A, or FOXO3a TM‐ER.ResultsA significant decrease in P‐Akt level and changes in iron metabolism were observed even in the group of ALS I animals. This was accompanied by an increase in the active form of FOXO3a, up‐regulation of atrogin‐1, and catalase. However, significant muscle atrophy was observed in ALS II animals. An increase in ferritin L and H was accompanied by a rise in PCBP1 and APP protein levels. In SH‐SY5Y cells stably expressing SOD1 or SOD1 G93A, we observed elevated levels of ferritin L and H and non‐haem iron. Interestingly, insulin treatment significantly down‐regulated ferritin L and H proteins in the cell. Conversely, cells transfected with small interfering RNA against Akt 1, 2, 3, respectively, showed a significant increase in the ferritin and FOXO3a levels. In order to assess the role of FOXO3a in the ferritin expression, we constructed a line of SH‐SY5Y cells that expressed a fusion protein made of FOXO3a fused at the C‐terminus with the ligand‐binding domain of the oestrogen receptor (TM‐ER) being activated by 4‐hydroxytamoxifen. Treatment of the cells with 4‐hydroxytamoxifen significantly up‐regulated ferritin L and H proteins level.ConclusionsOur data suggest that impairment of insulin signalling and iron metabolism in the skeletal muscle precedes muscle atrophy and is mediated by changes in Akt/FOXO3a signalling pathways.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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hmSOD1 gene mutation‐induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway

Halon-Golabek

Borkowska

Kaczor

et al. 2018

J cachexia sarcopenia muscle

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“…This regulatory feedback loop allows for local control over iron trafficking within the CNS, although the abundance of hepcidin in the brain interstitium suggests that at least some fraction of it is of systemic (likely hepatic) origin119. Low levels of ferroportin have been found in brains of patients with AD120, as well as in rat models of PD121 and ALS122. In a mouse model of MS, reduced expression of ferroportin and intracellular iron overload were specifically found in macrophage-like microglia, but not in astrocytes123.…”

Section: Iron and The Pathophysiology Of Diseasementioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

290

205

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Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available.

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“…In contrast, genetically engineered rats have only recently been developed to model disorders such as Alzheimer's disease [1][2][3], autism [4], Parkinson's disease [5][6][7][8], Huntington's disease [9,10], amyotrophic lateral sclerosis [11,12], and spinocerebellar ataxia [13]. In light of novel methods to manipulate the genome of rats [14][15][16] such as the CRISPR-Cas system [17], there will likely be future increases in the production and use of genetically engineered rats to model a variety of neurological disorders.…”

Section: Introductionmentioning

confidence: 90%

Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats

et al. 2015

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The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.

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

Cited by 22 publications

References 36 publications

hmSOD1 gene mutation‐induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway

hmSOD1 gene mutation‐induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway

Targeting iron metabolism in drug discovery and delivery

Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats

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