{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:48:27Z","timestamp":1790092107373,"version":"4.0.1"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,1,29]],"date-time":"2018-01-29T00:00:00Z","timestamp":1517184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2014\/13\/B\/NZ7\/02346"],"award-info":[{"award-number":["2014\/13\/B\/NZ7\/02346"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Recently, 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\u2013FOXO3a signalling pathway triggers changes in the iron metabolism in the muscles of transgenic animals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In the present study, we used transgenic rats bearing the G93A hmSOD1 gene and their non\u2010transgenic 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\u2010SY5Y and C2C12 cell lines stably transfected with pcDNA3.1, SOD1 WT and SOD1 G93A, or FOXO3a TM\u2010ER.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A significant decrease in P\u2010Akt 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\u2010regulation of atrogin\u20101, 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\u2010SY5Y cells stably expressing SOD1 or SOD1 G93A, we observed elevated levels of ferritin L and H and non\u2010haem iron. Interestingly, insulin treatment significantly down\u2010regulated 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\u2010SY5Y cells that expressed a fusion protein made of FOXO3a fused at the C\u2010terminus with the ligand\u2010binding domain of the oestrogen receptor (TM\u2010ER) being activated by 4\u2010hydroxytamoxifen. Treatment of the cells with 4\u2010hydroxytamoxifen significantly up\u2010regulated ferritin L and H proteins level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12283","type":"journal-article","created":{"date-parts":[[2018,1,29]],"date-time":"2018-01-29T23:22:41Z","timestamp":1517268161000},"page":"557-569","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["hmSOD1 gene mutation\u2010induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway"],"prefix":"10.1002","volume":"9","author":[{"given":"Malgorzata","family":"Halon\u2010Golabek","sequence":"first","affiliation":[{"name":"Department of Physiotherapy Medical University of Gdansk  Gdansk 80\u2010211 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andzelika","family":"Borkowska","sequence":"additional","affiliation":[{"name":"Department of Bioenergetics and Physiology of Exercise Medical University of Gdansk  Gdansk 80\u2010211 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan J.","family":"Kaczor","sequence":"additional","affiliation":[{"name":"Department of Bioenergetics and Physiology of Exercise Medical University of Gdansk  Gdansk 80\u2010211 Poland"},{"name":"Department of Neurobiology of Muscle Gdansk University of Physical Education and Sport  Gdansk 80\u2010336 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wieslaw","family":"Ziolkowski","sequence":"additional","affiliation":[{"name":"Department of Bioenergetics and Nutrition Gdansk University of Physical Education and Sport  Gdansk 80\u2010336 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian J.","family":"Flis","sequence":"additional","affiliation":[{"name":"Department of Bioenergetics and Physiology of Exercise Medical University of Gdansk  Gdansk 80\u2010211 Poland"},{"name":"Department of Bioenergetics and Nutrition Gdansk University of Physical Education and Sport  Gdansk 80\u2010336 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narcyz","family":"Knap","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry Medical University of Gdansk  Gdansk 80\u2010211 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajetan","family":"Kasperuk","sequence":"additional","affiliation":[{"name":"Department of Bioenergetics and Physiology of Exercise Medical University of Gdansk  Gdansk 80\u2010211 Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jedrzej","family":"Antosiewicz","sequence":"additional","affiliation":[{"name":"Department of Bioenergetics and Physiology of Exercise Medical University of Gdansk  Gdansk 80\u2010211 Poland"},{"name":"Department of Biochemistry Gdansk University of Physical Education and Sport  Gdansk 80\u2010336 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