Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance

Nat Commun. 2019 Jun 24;10(1):2767. doi: 10.1038/s41467-019-10712-0.


The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Aspartate Aminotransferases / metabolism
  • Aspartic Acid / metabolism
  • Carbidopa / pharmacology
  • Cell Respiration / drug effects
  • Cell Respiration / physiology
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Fatigue / physiopathology*
  • Glycolysis / physiology
  • Kynurenine / metabolism*
  • Malates / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Animal
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiopathology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Physical Conditioning, Animal / physiology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Transaminases / antagonists & inhibitors
  • Transaminases / metabolism


  • Malates
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Protein Isoforms
  • Aspartic Acid
  • Kynurenine
  • malic acid
  • Transaminases
  • Aspartate Aminotransferases
  • kynurenine-oxoglutarate transaminase
  • Carbidopa