Dietary Supplementation with α-Ketoglutarate Activates mTOR Signaling and Enhances Energy Status in Skeletal Muscle of Lipopolysaccharide-Challenged Piglets

J Nutr. 2016 Aug;146(8):1514-20. doi: 10.3945/jn.116.236000. Epub 2016 Jul 6.

Abstract

Background: Skeletal muscle undergoes rapid loss in response to inflammation. α-Ketoglutarate (AKG) has been reported to enhance muscle growth in piglets, but the underlying mechanisms are largely unknown.

Objectives: This study tested the hypothesis that dietary AKG supplementation activates mechanistic target of rapamycin (mTOR) signaling and improves skeletal muscle energy metabolism in lipopolysaccharide (LPS)-challenged piglets.

Methods: Forty-eight male piglets (Duroc × Landrace × Yorkshire) were weaned at 21 d of age to a corn- and soybean meal-based diet. After a 3-d period of adaptation, piglets with a mean weight of 7.21 kg were randomly assigned to control, LPS (intraperitoneal administration of 80 μg LPS/kg body weight on days 10, 12, 14, and 16), or LPS plus 1% dietary AKG (LPS+AKG) groups. On day 16, blood samples were collected from 8 piglets/group 3 h after LPS administration. On day 17, piglets were killed to obtain gastrocnemius muscle from 8 piglets/group for biochemical analysis.

Results: Compared with the control group, LPS administration increased (P < 0.05) plasma concentrations of globulin (by 14%) and tumor necrosis factor α (by 59%) and the intramuscular ratio of AMP to ATP (by 93%) and abundance of phosphorylated acetyl-coenzyme A carboxylase (ACC) β protein (by 64%). Compared with the control group, LPS administration reduced (P < 0.05) weight gain (by 15%); plasma concentrations of glutamine (by 20%), glucose (by 23%), insulin, insulin-like growth factor I, and epidermal growth factor; intramuscular concentrations of glutamine (by 27%), ATP (by 12%), ADP (by 22%), and total adenine nucleotides; and intramuscular ratios of phosphorylated mTOR to total mTOR (by 38%) and of phosphorylated 70-kDa ribosomal protein S6 kinase (p70S6K) to total p70S6K (by 39%). These adverse effects of LPS were ameliorated (P < 0.05) by AKG supplementation.

Conclusions: Dietary AKG supplementation activated mTOR signaling, inhibited ACC-β, and improved energy status in skeletal muscle of LPS-challenged piglets. These results provide a biochemical basis for the use of AKG to enhance piglet growth under inflammatory or practical postweaning conditions.

Keywords: cell signaling; gastrocnemius muscle; inflammation; lipopolysaccharide; α-ketoglutarate.

MeSH terms

  • Acetyl-CoA Carboxylase / metabolism
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Body Weight / drug effects
  • Dietary Supplements*
  • Energy Metabolism / drug effects*
  • Globulins / metabolism
  • Glutamine / metabolism
  • Inflammation / chemically induced
  • Inflammation / complications*
  • Inflammation / metabolism
  • Ketoglutaric Acids / pharmacology*
  • Lipopolysaccharides
  • Male
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy / etiology
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / prevention & control
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Swine
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Necrosis Factor-alpha / blood
  • Weaning

Substances

  • Globulins
  • Ketoglutaric Acids
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Glutamine
  • Adenosine Monophosphate
  • Adenosine Triphosphate
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Acetyl-CoA Carboxylase