MuRF1 deficiency prevents age-related fat weight gain, possibly through accumulation of PDK4 in skeletal muscle mitochondria in older mice

• Material Type: 博士論文
• Title: MuRF1 deficiency prevents age-related fat weight gain, possibly through accumulation of PDK4 in skeletal muscle mitochondria in older mice
• Author/Editor: Sugiura, Kosuke; Hirasaka, Katsuya; Maeda, Tasuku; Uchida, Takayuki; Kishimoto, Koji; Oarada, Motoko; Labeit, Siegfried; Ulla, Anayt; Sakakibara, Iori; Nakao, Reiko; Sairyo, Koichi; Nikawa, Takeshi
• Author Heading: Sugiura, Kosuke; Hirasaka, Katsuya; Maeda, Tasuku; Uchida, Takayuki; Kishimoto, Koji; Oarada, Motoko; Labeit, Siegfried; Ulla, Anayt; Sakakibara, Iori; Nakao, Reiko; Sairyo, Koichi; Nikawa, Takeshi
• Publication, Distribution, etc.: Wiley|Orthopaedic Research Society
• Publication Date: 2021-06-29
• Publication Date (W3CDTF): 2021-06-29
• Alternative Title: 老齢マウスにおいてMuRF1欠乏は筋ミトコンドリア内のPDK4蓄積を介して加齢による脂肪増加を抑制する; MuRF1 regulates lipid metabolism
• Periodical title: Journal of Orthopaedic Research
• No. or year of volume/issue: 40 5
• Volume: 40
• Issue: 5
• Pages: 1026-1038
• ISSN (Periodical Title): ISSN : 1554-527X
• Degree grantor/type: 徳島大学
• Date Granted: 2021-11-25
• Dissertation Number: 甲第3562号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Muscle atrophy; Muscle RING finger 1 (MuRF1); lipid metabolism; Pyruvate dehydrogenase kinase 4 (PDK4); SUMO modification
• Target Audience: 一般
• Note (General): Recent studies show that muscle mass and metabolic function are interlinked. Muscle RING finger 1 (MuRF1) is a critical muscle-specific ubiquitin ligase associated with muscle atrophy. Yet, the molecular target of MuRF1 in atrophy and aging remains unclear. We examined the role of MuRF1 in aging, using MuRF1-deficient (MuRF1–/–) mice in vivo, and MuRF1-overexpressing cell in vitro. MuRF1 deficiency partially prevents age-induced skeletal muscle loss in mice. Interestingly, body weight and fat mass of >7-month-old MuRF1–/– mice were lower than in MuRF1+/+ mice. Serum and muscle metabolic parameters and results of indirect calorimetry suggest significantly higher energy expenditure and enhanced lipid metabolism in 3-month-old MuRF1–/– mice than in MuRF1+/+ mice, resulting in suppressed adipose tissue gain during aging. Pyruvate dehydrogenase kinase 4 (PDK4) is crucial for a switch from glucose to lipid metabolism, and the interaction between MuRF1 and PDK4 was examined. PDK4 protein levels were elevated in mitochondria from the skeletal muscle in MuRF1–/– mice. In vitro, MuRF1 interacted with PDK4 but did not induce degradation through ubiquitination. Instead, SUMOylation of PDK4 was detected in MuRF1-overexpressing cells, in contrast to cells without the RING domain of MuRF1. MuRF1 deficiency enhances lipid metabolism possibly by upregulating PDK4 localization into mitochondrial through prevention of SUMOylation. Inhibition of MuRF1-mediated PDK4 SUMOylation is a potential therapeutic target for age-related dysfunction of lipid metabolism and muscle atrophy.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): © 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC
• Related Material (DOI): 10.1002/jor.25131
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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