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

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

Author information

1
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
2
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
3
Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
4
Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland.
5
Institute of Sports Science and Innovations, Lithuanian Sports University, Sporto str. 6, 44221, Kaunas, Lithuania.
6
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden. jorge.ruas@ki.se.

Abstract

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.

PMID:
31235694
PMCID:
PMC6591322
DOI:
10.1038/s41467-019-10712-0
[Indexed for MEDLINE]
Free PMC Article

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