Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance.
- Agudelo LZ Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Ferreira DMS Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Dadvar S Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Cervenka I Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Ketscher L Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Izadi M Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Zhengye L Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Furrer R Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland.
- Handschin C Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland.
- Venckunas T Institute of Sports Science and Innovations, Lithuanian Sports University, Sporto str. 6, 44221, Kaunas, Lithuania.
- Brazaitis M Institute of Sports Science and Innovations, Lithuanian Sports University, Sporto str. 6, 44221, Kaunas, Lithuania.
- Kamandulis S Institute of Sports Science and Innovations, Lithuanian Sports University, Sporto str. 6, 44221, Kaunas, Lithuania.
- Lanner JT Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.
- Ruas JL Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden. jorge.ruas@ki.se.
- 2019-06-26
Published in:
- 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
English
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1038/s41467-019-10712-0
- PMID 31235694
- Persistent URL
- https://sonar.ch/global/documents/92552
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