Kynurenine, a Tryptophan Metabolite That Increases with Age, Induces Muscle Atrophy and Lipid Peroxidation

Abstract

The cellular and molecular mechanisms underlying loss of muscle mass with age (sarcopenia) are not well-understood; however, heterochronic parabiosis experiments show that circulating factors are likely to play a role. Kynurenine (KYN) is a circulating tryptophan metabolite that is known to increase with age and is a ligand of the aryl hydrocarbon receptor (Ahr). Here, we tested the hypothesis that KYN activation of Ahr plays a role in muscle loss with aging. Results indicate that KYN treatment of mouse and human myoblasts increased levels of reactive oxygen species (ROS) 2-fold and KYN treatment in vivo reduced muscle size and strength and increased muscle lipid peroxidation in young mice. PCR array data indicate that muscle fiber size reduction with KYN treatment reduces protein synthesis markers whereas ubiquitin ligase gene expression is not significantly increased. KYN is generated by the enzyme indoleamine 2,3-dioxygenase (IDO), and aged mice treated with the IDO inhibitor 1-methyl-D-tryptophan showed an increase in muscle fiber size and muscle strength. Small-molecule inhibition of Ahr in vitro, and Ahr knockout in vivo, did not prevent KYN-induced increases in ROS, suggesting that KYN can directly increase ROS independent of Ahr activation. Protein analysis identified very long-chain acyl-CoA dehydrogenase as a factor activated by KYN that may increase ROS and lipid peroxidation. Our data suggest that IDO inhibition may represent a novel therapeutic approach for the prevention of sarcopenia and possibly other age-associated conditions associated with KYN accumulation such as bone loss and neurodegeneration.

Antioxidant Apigenin Relieves Age-Related Muscle Atrophy by Inhibiting Oxidative Stress and Hyperactive Mitophagy and Apoptosis in Skeletal Muscle of Mice

“…Pharmaceutical and nonpharmaceutical ways have been proposed to prevent and treat skeletal muscle atrophy ( 5 , 11 ). For example, beneficial effect of butyrate on muscle mass during aging is suggested by reduced markers of oxidative stress and apoptosis and improved antioxidant enzyme activity ( 12 ). Kynurenine capable of increasing ROS is generated by indoleamine 2,3-dioxygenase (IDO), and myofiber size and muscle strength are increased by treatment with the IDO inhibitor 1-methyl-D-tryptophan in aged mice with sarcopenia ( 7 ).…”

Association between suicide risk severity and sarcopenia in non-elderly Chinese inpatients with major depressive disorder

“…While chronic low-grade inflammation might increase muscle catabolism, which is one of the pathophysiological characteristics of sarcopenia [42]. Further, these pro-inflammatory cytokines can activate kynurenine pathway [43][44][45], increase the level of quinolinic acid, the NMDA receptor agonist, and simultaneously decrease neuroprotective metabolites via glutamate neurotransmission and neuroinflammation [46].…”

Association between suicide risk severity and sarcopenia in non-elderly Chinese inpatients with major depressive disorder

“…While chronic low-grade inflammation might increase muscle catabolism, which is one of the pathophysiological characteristics of sarcopenia [51]. Further, these pro-inflammatory cytokines can activate kynurenine pathway [52][53][54], increase the level of quinolinic acid, the NMDA receptor agonist, and simultaneously decrease neuroprotective metabolites via glutamate neurotransmission and neuroinflammation [55]. Whereas physical exercise induces the release of PGC-1α1 in skeletal muscle that increases the expression of kynurenine aminotransferases, thus promoting the conversion of kynurenine into kynurenic acid, a metabolite unable to pass the blood-brain barrier, and protecting the brain from stress-induced changes, which can be instrumental in relieving depression and suicide ideation [56].…”