title: Docosahexaenoic acid-mediated protein aggregates may reduce proteasome activity and delay myotube degradation during muscle atrophy in vitro.
abstract: Proteasomes are the primary degradation machinery for oxidatively damaged proteins that compose a class of misfolded protein substrates. Cellular levels of reactive oxygen species increase with age and this cellular propensity is particularly harmful when combined with the age-associated development of various human disorders including cancer, neurodegenerative disease and muscle atrophy. Proteasome activity is reportedly downregulated in these disease conditions. Herein, we report that docosahexaenoic acid (DHA), a major dietary omega-3 polyunsaturated fatty acid, mediates intermolecular protein cross-linkages through oxidation, and the resulting protein aggregates potently reduce proteasomal activity both in vitro and in cultured cells. Cellular models overexpressing aggregation-prone proteins such as tau showed significantly elevated levels of tau aggregates and total ubiquitin conjugates in the presence of DHA, thereby reflecting suppressed proteasome activity. Strong synergetic cytotoxicity was observed when the cells overexpressing tau were simultaneously treated with DHA. Antioxidant N-acetyl cysteine significantly desensitized the cells to DHA-induced oxidative stress. DHA significantly delayed the proteasomal degradation of muscle proteins in a cellular atrophy model. Thus, the results of our study identified DHA as a potent inducer of cellular protein aggregates that inhibit proteasome activity and potentially delay systemic muscle protein degradation in certain pathologic conditions.
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin, Korea.
authors.forename: Seung Kyun
authors.initials: SK
authors.lastname: Shin
authors.affiliation: Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jung Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Son
authors.affiliation: Department of Chemistry, College of Science, Korea University, Seoul, Korea.
authors.forename: Min Wook
authors.initials: MW
authors.lastname: Lee
authors.affiliation: Department of Chemistry, College of Science, Korea University, Seoul, Korea.
authors.forename: Hak Joong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin, Korea.
authors.forename: Sue Ah
authors.initials: SA
authors.lastname: Noh
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin, Korea.
authors.forename: Kwang Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Min Jae
authors.identifier: 0000-0002-3252-6467
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D009133:Muscular Atrophy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000975:Antioxidants; C078433:FLI1 protein, human; D009124:Muscle Proteins; D066329:Protein Aggregates; D051789:Proto-Oncogene Protein c-fli-1; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D025801:Ubiquitin; D016875:tau Proteins; D004281:Docosahexaenoic Acids; D046988:Proteasome Endopeptidase Complex