Open AccessDocosahexaenoic acid counteracts palmitate‐induced endoplasmic reticulum stress in C2C12 myotubes: Impact on muscle atrophy
Author(s) -
WoodworthHobbs Myra E.,
Perry Ben D.,
Rahnert Jill A.,
Hudson Matthew B.,
Zheng Bin,
Price S. Russ
Publication year - 2017
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13530
Subject(s) - unfolded protein response , myogenesis , docosahexaenoic acid , endoplasmic reticulum , autophagy , xbp1 , muscle atrophy , atg5 , biology , protein kinase a , fatty acid synthase , microbiology and biotechnology , chemistry , skeletal muscle , medicine , kinase , endocrinology , biochemistry , fatty acid , apoptosis , polyunsaturated fatty acid , rna , rna splicing , gene
Lipid accumulation in skeletal muscle results in dysregulation of protein metabolism and muscle atrophy. We previously reported that treating C2C12 myotubes with palmitate ( PA ), a saturated fatty acid, increases the overall rate of proteolysis via activation of the ubiquitin‐proteasome and autophagy systems; co‐treatment with the omega‐3 polyunsaturated fatty acid docosahexaenoic acid ( DHA ) prevents the PA ‐induced responses. Others have reported that PA induces endoplasmic reticulum ( ER ) stress which initiates the unfolded protein response ( UPR ), a collective group of responses that can lead to activation of caspase‐mediated proteolysis and autophagy. Presently, we tested the hypothesis that DHA protects against PA ‐induced ER stress/ UPR and its atrophy‐related responses in muscle cells. C2C12 myotubes were treated with 500 μ mol/L PA and/or 100 μ mol/L DHA for 24 h. Proteins and mRNA associated with ER stress/ UPR , autophagy, and caspase‐3 activation were evaluated. PA robustly increased the phosphorylation of protein kinase R ( PKR )‐like ER kinase ( PERK ) and eukaryotic initiation factor 2 α ( eIF 2 α ). It also increased the mRNA s encoding activating transcription factor 4 ( ATF 4), spliced X‐box binding protein 1 ( XBP 1s), C/ EBP homologous protein ( CHOP ), and autophagy‐related 5 (Atg5) as well as the protein levels of the PERK target nuclear factor erythroid 2‐related factor (Nrf2), CHOP , and cleaved (i.e., activated) caspase‐3. Co‐treatment with DHA prevented all of the PA ‐induced responses. Our results indicate that DHA prevents PA ‐induced muscle cell atrophy, in part, by preventing ER stress/ UPR , a process that leads to activation of caspase‐mediated proteolysis and an increase in expression of autophagy‐related genes.