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

Leandro Z. Agudelo, Duarte M. S. Ferreira, Shamim Dadvar, Igor Cervenka, Lars Ketscher, Manizheh Izadi, Liu Zhengye, Regula Furrer, Christoph Handschin, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Johanna T. Lanner and Jorge L. Ruas ()
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Leandro Z. Agudelo: Karolinska Institutet
Duarte M. S. Ferreira: Karolinska Institutet
Shamim Dadvar: Karolinska Institutet
Igor Cervenka: Karolinska Institutet
Lars Ketscher: Karolinska Institutet
Manizheh Izadi: Karolinska Institutet
Liu Zhengye: Karolinska Institutet
Regula Furrer: University of Basel
Christoph Handschin: University of Basel
Tomas Venckunas: Lithuanian Sports University
Marius Brazaitis: Lithuanian Sports University
Sigitas Kamandulis: Lithuanian Sports University
Johanna T. Lanner: Karolinska Institutet
Jorge L. Ruas: Karolinska Institutet

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10712-0

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