Agudelo LZ Ferreira DMS Dadvar S Cervenka I Ketscher L Izadi M Zhengye L Furrer R Handschin C Venckunas T Brazaitis M Kamandulis S Lanner JT Ruas JL 2019 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. application/pdf https://sonar.ch/global/documents/92552 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-019-10712-0 info:eu-repo/semantics/altIdentifier/pmid/31235694 info:eu-repo/semantics/openAccess Nature communications. - 2019 Adaptation, Physiological Animals Aspartate Aminotransferases Aspartic Acid Carbidopa Cell Respiration Energy Metabolism Fatigue Glycolysis Kynurenine Malates Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Models, Animal Muscle, Skeletal Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Physical Conditioning, Animal Protein Isoforms Transaminases Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance. http://purl.org/coar/resource_type/c_6501