Iron-induced skeletal muscle atrophy involves an Akt-forkhead box O3-E3 ubiquitin ligase-dependent pathway

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• 作者：Yasumasa Ikeda^a ; ¹ ; ^{yasuike@tokushima-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Mizuki Imao^b ; ¹ ; Akiho Satoh^b ; Hiroaki Watanabe^c ; Hirofumi Hamano^a ; ^d ; Yuya Horinouchi^a ; ^d ; Yuki Izawa-Ishizawa^a ; Yoshitaka Kihira^a ; Licht Miyamoto^b ; Keisuke Ishizawa^c ; ^d ; Koichiro Tsuchiya^b ; Toshiaki Tamaki^a
• 关键词：Iron ; Skeletal muscle atrophy ; Atrogenes
• 刊名：Journal of Trace Elements in Medicine and Biology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：35
• 期：Complete
• 页码：66-76
• 全文大小：3531 K

文摘

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.