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DOI	10.1073/pnas.2102895118
	Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy
	Liu L.; Koike H.; Ono T.; Hayashi S.; Kudo F.; Kaneda A.; Kagechika H.; Manabe I.; Nakashima T.; Oishi Y.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:35
英文摘要	Skeletal muscle atrophy is caused by various conditions, including aging, disuse related to a sedentary lifestyle and lack of physical activity, and cachexia. Our insufficient understanding of the molecular mechanism underlying muscle atrophy limits the targets for the development of effective pharmacologic treatments and preventions. Here, we identified Krüppel-like factor 5 (KLF5), a zinc-finger transcription factor, as a key mediator of the early muscle atrophy program. KLF5 was up-regulated in atrophying myotubes as an early response to dexamethasone or simulated microgravity in vitro. Skeletal muscle-selective deletion of Klf5 significantly attenuated muscle atrophy induced by mechanical unloading in mice. Transcriptome- and genome-wide chromatin accessibility analyses revealed that KLF5 regulates atrophy-related programs, including metabolic changes and E3-ubiquitin ligase-mediated proteolysis, in coordination with Foxo1. The synthetic retinoic acid receptor agonist Am80, a KLF5 inhibitor, suppressed both dexamethasone- and microgravity-induced muscle atrophy in vitro and oral Am80 ameliorated disuse-and dexamethasone-induced atrophy in mice. Moreover, in three independent sets of transcriptomic data from human skeletal muscle, KLF5 expression significantly increased with age and the presence of sarcopenia and correlated positively with the expression of the atrophy-related ubiquitin ligase genes FBXO32 and TRIM63. These findings demonstrate that KLF5 is a key transcriptional regulator mediating muscle atrophy and that pharmacological intervention with Am80 is a potentially preventive treatment. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	KLF; Muscle atrophy; RAR ligand
语种	英语
scopus关键词	benzoic acid; dexamethasone; Fbxo32 protein, mouse; glucocorticoid; Klf5 protein, mouse; kruppel like factor; muscle protein; tamibarotene; tetralin derivative; Trim63 protein, mouse; tripartite motif protein; ubiquitin protein ligase; animal; C57BL mouse; drug development; drug effect; gene expression regulation; genetics; knockout mouse; male; metabolism; mouse; muscle atrophy; pathology; physiology; signal transduction; skeletal muscle; Animals; Benzoates; Dexamethasone; Drug Development; Gene Expression Regulation; Glucocorticoids; Kruppel-Like Transcription Factors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Signal Transduction; SKP Cullin F-Box Protein Ligases; Tetrahydronaphthalenes; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251037
作者单位	Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, 113-8602, Japan; Department of Cellular and Molecular Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8551, Japan; Department of Systems Medicine, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan; Department of Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan; Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan
推荐引用方式 GB/T 7714	Liu L.,Koike H.,Ono T.,et al. Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy[J],2021,118(35).
APA	Liu L..,Koike H..,Ono T..,Hayashi S..,Kudo F..,...&Oishi Y..(2021).Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy.Proceedings of the National Academy of Sciences of the United States of America,118(35).
MLA	Liu L.,et al."Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy".Proceedings of the National Academy of Sciences of the United States of America 118.35(2021).