Docosahexaenoic acid prevents palmitate-induced activation of proteolytic systems in C2C12 myotubes.
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.
Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA; Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA. Electronic address: mewoodw@emory.edu.
Myra E
ME
Woodworth-Hobbs
Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA.
Matthew B
MB
Hudson
Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA.
Jill A
JA
Rahnert
Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA.
Bin
B
Zheng
Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA.
Harold A
HA
Franch
Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA; Atlanta VA Medical Center, Decatur, GA, USA.
S Russ
SR
Price
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009133:Muscular Atrophy / Q000473:pathology; D010168:Palmitates / Q000009:adverse effects*; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C508686:BNip3 protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C480860:Map1lc3b protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D010168:Palmitates; D011506:Proteins; D004281:Docosahexaenoic Acids; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D051057:Proto-Oncogene Proteins c-akt
Docosahexaenoic acid; FoxO3; Macroautophagy; Muscle atrophy; Palmitate; Proteolysis