Docosahexaenoic acid attenuates palmitate‐induced unfolded protein response in myotubes (1163.21)

Abstract

Accumulation of saturated fatty acids in skeletal muscle results in dysregulation of protein metabolism and muscle atrophy. In cultured myotubes, the saturated fatty acid palmitate (PA) stimulates protein degradation and decreases cell size, while co‐treatment with the omega‐3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents the response. It has been shown that PA also induces endoplasmic reticulum stress and activates the unfolded protein response (UPR) in myotubes, resulting in decreased protein synthesis. The objective of this study is to test whether DHA protects against palmitate‐induced endoplasmic reticulum stress and activation of the UPR. C2C12 myotubes were treated with 500μM PA and/or 100μM DHA for 24h and protein markers of the UPR were evaluated by western analysis. PA induced activation of protein kinase R‐like protein kinase (PERK), as indicated by an increased phospho‐PERK:total PERK ratio. PA also induced phosphorylation and inactivation of eukaryotic initiation factor 2α (eIF2α). While co‐treatment with DHA attenuated the effects of PA on PERK ratio, eIF2α phosphorylation was similar in myotubes treated with PA and PA+DHA. These results indicate that DHA attenuates the effects of PA on activation of the UPR but does not restore global protein synthesis; this suggests that DHA restores myotube diameter primarily by inhibiting palmitate‐induced protein degradation.Grant Funding Source: Supported by NIH RO1DK95610, AHA GRNT7660020, and VA MERIT X01BX001456 awarded to SR Price.