Exp Mol Med.
2017 Jan;49(1):e287. 10.1038/emm.2016.133.
Docosahexaenoic acid-mediated protein aggregates may reduce proteasome activity and delay myotube degradation during muscle atrophy in vitro
- Affiliations
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- 1Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin, Korea.
- 2Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. minjlee@snu.ac.kr
- 3Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
- 4Department of Chemistry, College of Science, Korea University, Seoul, Korea.
- KMID: 2367533
- DOI: http://doi.org/10.1038/emm.2016.133
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.
MeSH Terms
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Atrophy
Cells, Cultured
Cysteine
Humans
In Vitro Techniques*
Muscle Fibers, Skeletal*
Muscle Proteins
Muscular Atrophy*
Neurodegenerative Diseases
Oxidative Stress
Proteasome Endopeptidase Complex*
Protein Aggregates*
Reactive Oxygen Species
Ubiquitin
Cysteine
Muscle Proteins
Proteasome Endopeptidase Complex
Protein Aggregates
Reactive Oxygen Species
Ubiquitin
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