title: Iron-induced skeletal muscle atrophy involves an Akt-forkhead box O3-E3 ubiquitin ligase-dependent pathway.
abstract: Skeletal muscle wasting or sarcopenia is a critical health problem. Skeletal muscle atrophy is induced by an excess of iron, which is an essential trace metal for all living organisms. Excessive amounts of iron catalyze the formation of highly toxic hydroxyl radicals via the Fenton reaction. However, the molecular mechanism of iron-induced skeletal muscle atrophy has remained unclear. In this study, 8-weeks-old C57BL6/J mice were divided into 2 groups: vehicle-treated group and the iron-injected group (10 mg iron day(-1)mouse(-1)) during 2 weeks. Mice in the iron-injected group showed an increase in the iron content of the skeletal muscle and serum and ferritin levels in the muscle, along with reduced skeletal muscle mass. The skeletal muscle showed elevated mRNA expression of the muscle atrophy-related E3 ubiquitin ligases, atrogin-1 and muscle ring finger-1(MuRF1), on days 7 and 14 of iron treatment. Moreover, iron-treated mice showed reduced phosphorylation of Akt and forkhead box O3 (FOXO3a) in skeletal muscles. Inhibition of FOXO3a using siRNA in vitro in C2C12 myotube cells inhibited iron-induced upregulation of atrogin-1 and MuRF1 and reversed the reduction in myotube diameters. Iron-load caused oxidative stress, and an oxidative stress inhibitor abrogated iron-induced muscle atrophy by reactivating the Akt-FOXO3a pathway. Iron-induced skeletal muscle atrophy is suggested to involve the E3 ubiquitin ligase mediated by the reduction of Akt-FOXO3a signaling by oxidative stress.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. Electronic address: yasuike@tokushima-u.ac.jp.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Imao
authors.affiliation: Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Akiho
authors.initials: A
authors.lastname: Satoh
authors.affiliation: Department of Clinical Pharmacy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamano
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Horinouchi
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Izawa-Ishizawa
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kihira
authors.affiliation: Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Licht
authors.initials: L
authors.lastname: Miyamoto
authors.affiliation: Department of Clinical Pharmacy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D005293:Ferritins / Q000097:blood; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D007501:Iron / Q000009:adverse effects*; D019190:Iron Overload / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000097:blood / Q000139:chemically induced*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D009124:Muscle Proteins; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D005293:Ferritins; D007501:Iron; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt
keywords: Atrogenes; Iron; Skeletal muscle atrophy