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タイトル: Blockade of angiotensin II modulates insulin-like growth factor 1-mediated skeletal muscle homeostasis in experimental steatohepatitis
その他のタイトル: 脂肪肝炎において、アンギオテンシンⅡ受容体の遮断はIGF-1を介した骨格筋ホメオスタシスを調整する
著者: Tanaka, Misako
Kaji, Kosuke
Nishimura, Norihisa
Asada, Shohei
Koizumi, Aritoshi
Matsuda, Takuya
Yorioka, Nobuyuki
Tsuji, Yuki
Fujinaga, Yukihisa
Sato, Shinya
Namisaki, Tadashi
Akahane, Takemi
Yoshiji, Hitoshi
キーワード: Sarcopenia
Nonalcoholic steatohepatitis
Angiotensin II
Insulin-like growth factor 1
発行日: 2024年2月
出版者: Elsevier
引用: Biochimica et biophysica acta. Molecular cell research. 2024 Feb, vol.1871, no.2, article no.119649
抄録: Sarcopenia is associated with mortality in patients with nonalcoholic steatohepatitis (NASH). Angiotensin Ⅱ receptor blocker (ARB) has been suggested to prevent sarcopenia, but reports on its effect on NASH-derived skeletal muscle atrophy in conjunction with insulin-like growth factor 1 (IGF-1)-mediated muscle homeostasis are few. Our aim was to examine the combined effect of the ARB losartan and IGF-1 replacement on skeletal muscle atrophy in a methionine–choline deficient (MCD) diet-fed murine steatohepatitis model. The MCD-fed mice developed steatohepatitis and skeletal muscle atrophy, as indicated by the reduction of psoas muscle mass and attenuation of forelimb and hindlimb grip strength. Significantly suppressed steatohepatitis and skeletal muscle atrophy was observed after single treatment with ARB or IGF-1, and these effects were augmented after combination treatment. Treatment with ARB and IGF-1 effectively inhibited ubiquitin proteasome-mediated protein degradation by reducing forkhead box protein O1 (FOXO1) and FOXO3a tran scriptional activity in the skeletal muscle. Combined ARB and IGF-1 decreased the intramuscular expression of proinflammatory cytokines (i.e., TNFα, IL6, and IL1β) and increased the Trolox equivalent antioxidant capacity and antioxidant enzymes (CAT, GPX1, SOD2, and CYTB). This antioxidant effect was based on downregulation of NADPH oxidase (NOX) 2, normalization of mitochondrial biogenesis and dynamics. Moreover, ARB increased the hepatic and plasma IGF-1 levels and improved steatohepatitis, leading to enhanced skeletal muscle protein synthesis mediated by IGF-1/ AKT/ mechanistic target of rapamycin signaling. Collectively, combined ARB and IGF-1 replacement could be a promising new therapeutic target for NASH-derived skeletal muscle wasting.
内容記述: 権利情報:© 2023 Elsevier B.V. All rights reserved.
URI: http://hdl.handle.net/10564/4451
ISSN: 1879-2596
DOI: https://doi.org/10.1016/j.bbamcr.2023.119649
学位授与番号: 24601甲第956号
学位授与年月日: 2025-03-14
学位名: 博士(医学)
学位授与機関: 奈良県立医科大学
出現コレクション:2024年度

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