Docosahexaenoic acid prevents palmitate-induced activation of proteolytic systems in C2C12 myotubes

• Type of Material: Article
• Authors: Myra Woodworth-Hobbs, Emory University; Matthew B. Hudson, Emory University; Jill A. Rahnert, Emory University; Bin Zheng, Emory University; Harold Franch, Emory University; Stephen Price, Emory University
• Language: English
• Date: 2014-08-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jnutbio.2014.03.017
• Title of Journal or Parent Work: Journal of Nutritional Biochemistry
• ISSN: 0955-2863
• Volume: 25
• Issue: 8
• Start Page: 868
• End Page: 874
• Grant/Funding Information: This work was supported by NIH RO1DK95610, AHA GRNT7660020 and VA MERIT X01BX001456 awarded to S. Russ Price.
• Keywords: GLUCOSE-TOLERANCE; INSULIN; Docosahexaenoic acid; PROTEIN-SYNTHESIS; SIGNALING PATHWAYS; UBIQUITIN LIGASES; Palmitate; FoxO3; EXPRESSION; Nutrition & Dietetics; CELLS; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Macroautophagy; POLYUNSATURATED FATTY-ACIDS; Proteolysis; Muscle atrophy; FOXO TRANSCRIPTION FACTORS; Science & Technology; SKELETAL-MUSCLE ATROPHY
• Research Categories: Chemistry, Biochemistry

Abstract

Saturated fatty acids like palmitate contribute to muscle atrophy in a number of conditions (e.g., type II diabetes) by altering insulin signaling. Akt is a key modulator of protein balance that inhibits the FoxO transcription factors (e.g., FoxO3) which selectively induce the expression of atrophy-inducing genes (atrogenes) in the ubiquitin-proteasome and autophagy-lysosome systems. Conversely, omega-3 polyunsaturated fatty acids have beneficial effects on insulin signaling and may preserve muscle mass. In an earlier report, the omega-3 fatty acid docosahexaenoic acid (DHA) protected myotubes from palmitate-induced atrophy; the mechanisms underlying the alterations in protein metabolism were not identified. This study investigated whether DHA prevents a palmitate-induced increase in proteolysis by restoring Akt/FoxO signaling. Palmitate increased the rate of protein degradation, while cotreatment with DHA prevented the response. Palmitate reduced the activation state of Akt and increased nuclear FoxO3 protein while decreasing its cytosolic level. Palmitate also increased the messenger RNAs (mRNAs) of two FoxO3 atrogene targets, the E3 ubiquitin ligase atrogin-1/MAFbx and the autophagy mediator Bnip3. DHA attenuated the effects of palmitate on Akt activation, FoxO3 localization and atrogene mRNAs. DHA, alone or in combination with palmitate and decreased the ratio of LC3B-II:LC3B-I protein as well as the rate of autophagosome formation, as indicated by reduced LC3B-II protein in the presence of 10 mmol/L methylamine, suggesting an independent effect of DHA on the macroautophagy pathway. These data indicate that palmitate induces myotube atrophy, at least in part, by activating multiple proteolytic systems and that DHA counters the catabolic effects of palmitate by restoring Akt/FoxO signaling.