| First Author | Agudelo LZ | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 2767 |
| PubMed ID | 31235694 | Mgi Jnum | J:278513 |
| Mgi Id | MGI:6323763 | Doi | 10.1038/s41467-019-10712-0 |
| Citation | Agudelo LZ, et al. (2019) Skeletal muscle PGC-1alpha1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance. Nat Commun 10(1):2767 |
| abstractText | The coactivator PGC-1alpha1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1alpha1 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-1alpha1 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-1alpha1-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-1alpha1 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. |
