Docosahexaenoic acid-mediated protein aggregates may reduce proteasome activity and delay myotube degradation during muscle atrophy in vitro

Seung Kyun Shin, Ji Hyeon Kim, Jung Hoon Lee, Young Hoon Son, Min Wook Lee, Hak Joong Kim, Sue Ah Noh, Kwang Pyo Kim, In Gyu Kim, Min Jae Lee

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Article numbere287
JournalExperimental and Molecular Medicine
Volume49
Issue number1
DOIs
Publication statusPublished - 2017 Jan 13

Bibliographical note

Funding Information:
This work was supported by the grants of the Health Industry Development Institute (HI14C0202 to MJL), the National Research Foundation (2016R1C1B2011367 to JHL, 2016R1A2B2006507 to MJL, 2015R1D1A1A01056815 to HJK), the Bio and Medical Technology Development Program (2012M3A9B6055305 to KPK), and the Brain Research Program (2016M3C7A1913895 to MJL).

Funding Information:
This work was supported by the grants of the Health Industry Development Institute (HI14C0202 to MJL), the National Research Foundation (2016R1C1B2011367 to JHL, 2016R1A2B2006507 to MJL, 2015R1D1A1A01056815 to HJK), the Bio and Medical Technology Development Program (2012M3A9B6055305 to KPK), and the Brain Research Program (2016M3C7A1913895 to MJL). This work was also supported by the Creative-Pioneering Researchers Program through Seoul National University (SNU) and the Doosan Yonkang Foundation Cancer Research Grant through SNU Hospital (to MJL).

Publisher Copyright:
© 2017 KSBMB. All rights reserved.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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