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Inducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice

dc.contributor.authorSoyoung Park
dc.contributor.authorJin Ki Jung
dc.contributor.authorJung-Yoon Heo
dc.contributor.authorThemis Thoudam
dc.contributor.authorSu-Yeon Jeong
dc.contributor.authorSeok-Hui Kang
dc.contributor.authorChang-Hoon Woo
dc.contributor.authorHyoung Chul Choi
dc.contributor.authorIn-kyu Lee
dc.contributor.authorJinmyoung Dan
dc.contributor.authorJongsoon Lee
dc.contributor.authorJae-Ryong Kim
dc.contributor.authorSo-Young Park
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
dc.contributor.otherResearch Institute of Aging and Metabolism at Kyungpook National University, Daegu, 41404, Republic of Korea
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea
dc.contributor.otherResearch Institute of Aging and Metabolism at Kyungpook National University, Daegu, 41404, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
dc.contributor.otherDepartment of Orthopedic Surgery, College of Medicine, CHA University, Gumi, 39295, Republic of Korea
dc.contributor.otherSoonchunhyang Institute of Medi-Bio Science (SIMS) and Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea; Corresponding author. Soonchunhyang Institute of Medi-Bio Science (SIMS) and Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea.
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea; Corresponding author. Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea.
dc.contributor.otherSenotherapy-based Metabolic Diseases Control Research Center, Republic of Korea; Department of Physiology, College of Medicine, Yeungnam University, Daegu, 42415, Republic of Korea; Corresponding author. Department of Physiology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Nam-Gu, Daegu, 42415, Republic of Korea.
dc.date.accessioned2025-08-27T04:49:32Z
dc.date.accessioned2025-10-08T08:26:54Z
dc.date.available2025-10-08T08:26:54Z
dc.date.issued01-10-2025
dc.identifier.urihttp://digilib.fisipol.ugm.ac.id/repo/handle/15717717/35900
dc.description.abstractp53 has been implicated in metabolic regulation, but its role in obesity-induced skeletal muscle insulin resistance remains incompletely understood. This study aimed to determine the functional contribution of skeletal muscle p53 to insulin resistance and mitochondrial dysfunction, particularly in the context of obesity. We demonstrate that inducible, skeletal muscle-specific deletion of p53 (iMp53 KO) significantly improves insulin sensitivity in high-fat diet (HFD)-induced obese mice, with no effect in chow-fed controls. This metabolic improvement was accompanied by enhanced mitochondrial respiration and membrane potential, as well as reduced mitochondrial calcium overload in palmitate-treated C2C12 myotubes. Electron microscopy and immunoblotting revealed a marked reduction in mitochondria-associated membrane (MAM) area and decreased levels of MAM components (IP3R, VDAC, GRP75) in iMp53 KO muscle. Co-immunoprecipitation assays demonstrated physical interactions between p53 and MAM proteins, supporting a role for p53 in promoting MAM formation under obese conditions. Consistently, skeletal muscle from patients with type 2 diabetes exhibited elevated expression of both p53 and MAM markers, with a positive correlation between them. These findings suggest that p53 plays an important role in modulating ER–mitochondrial contacts and mitochondrial homeostasis in skeletal muscle and suggest its contribution to obesity-induced insulin resistance. This study provides new mechanistic insight into the pathological role of p53 in muscle metabolism.
dc.language.isoEN
dc.publisherElsevier
dc.subject.lccMedicine (General)
dc.titleInducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice
dc.typeArticle
dc.description.keywordsp53
dc.description.keywordsSkeletal muscle
dc.description.keywordsMitochondria-associated membrane
dc.description.keywordsInsulin resistance
dc.description.keywordsObesity
dc.description.doi10.1016/j.redox.2025.103828
dc.title.journalRedox Biology
dc.identifier.e-issn2213-2317
dc.identifier.oai9dbc0b7eba3d4733b5de11680794da50


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