Fish oil increases muscle protein mass and modulates Akt/FOXO, TLR4, and NOD signaling in weanling piglets after lipopolysaccharide challenge

J Nutr. 2013 Aug;143(8):1331-9. doi: 10.3945/jn.113.176255. Epub 2013 Jun 5.


Proinflammatory cytokines play a key role in the pathophysiology of muscle atrophy. In addition, n3 polyunsaturated fatty acids (PUFAs) exert an inhibitory effect on proinflammatory cytokines affecting many inflammatory diseases. We hypothesized that dietary supplementation of fish oil could attenuate lipopolysaccharide (LPS)-induced muscle atrophy. Weanling pigs were used in a 2 × 2 factorial design and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). After 21 d of treatment with either fish oil or corn oil, pigs received an i.p. injection of either saline or LPS. At 4 h postinjection, blood and muscle samples were obtained. Fish oil led to enrichment of eicosapentaenoic acid, docosahexaenoic acid, and total n3 PUFAs in muscles. Fish oil increased muscle protein mass, indicated by a higher protein:DNA ratio in gastrocnemius and longissimus dorsi (LD) muscles. In addition, fish oil increased Akt1 mRNA abundance and decreased Forkhead Box O (FOXO) 1 and FOXO4 mRNA abundance. Fish oil also increased phosphorylation of Akt and FOXO1 in gastrocnemius and LD muscles. Fish oil decreased the mRNA abundance of muscle atrophy F-box (MAFbx) and muscle RING finger 1 in gastrocnemius and LD muscles. Moreover, fish oil reduced the plasma tumor necrosis factor (TNF) α, muscle TNFα, and prostaglandin E2 concentrations, and muscle TNFα and cyclooxygenase 2 (COX2) mRNA abundance. Finally, fish oil downregulated the mRNA abundance of muscle toll-like receptor (TLR4) and its downstream signaling molecules [myeloid differentiation factor 88 (MyD88), TNFα receptor-associated factor 6 (TRAF6), and NF-κB p65], and nucleotide-binding oligomerization domain protein (NOD1), NOD2, and their adaptor molecule [receptor-interacting serine/threonine-protein kinase 2 (RIPK2)]. These results indicate fish oil may suppress muscle proinflammatory cytokine production via regulation of TLR and NOD signaling pathways and therefore improve muscle protein mass, possibly through maintenance of Akt/FOXO signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Docosahexaenoic Acids / administration & dosage
  • Eicosapentaenoic Acid / administration & dosage
  • Fish Oils / administration & dosage*
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Lipopolysaccharides / adverse effects
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nod1 Signaling Adaptor Protein / genetics
  • Nod1 Signaling Adaptor Protein / metabolism
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*
  • Swine
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Fish Oils
  • Forkhead Transcription Factors
  • Lipopolysaccharides
  • Muscle Proteins
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Nod1 Signaling Adaptor Protein
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • Cyclooxygenase 2
  • Proto-Oncogene Proteins c-akt