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The effects of kynurenine metabolites on skeletal muscle in vivo and in vitro
Author(s) -
Kaiser Helen,
Ding Ke-Hong,
Isales Carlos,
Hamrick Mark
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02936
Subject(s) - kynurenine , quinolinic acid , skeletal muscle , kynurenic acid , chemistry , kynurenine pathway , metabolite , oxidative stress , picolinic acid , in vivo , biochemistry , endocrinology , medicine , myocyte , tryptophan , biology , amino acid , microbiology and biotechnology
The cellular and molecular mechanisms underlying loss of muscle mass and strength with age (sarcopenia) are not well‐understood. Kynurenine (KYN) is a circulating tryptophan metabolite that is generated by the enzyme Indoleamine, 2, 3 dioxygenase (IDO), is known to increase with age, and is implicated in several age‐related pathologies. We have previously shown that an increase in KYN in young mice increased oxidative stress and decreased skeletal muscle mass, whereas inhibition of KYN using a small‐molecule inhibitor of IDO 1‐methyl‐D‐tryptophan (1MT) protected mice against the loss of muscle mass and strength with age. There are, however, a number of downstream metabolites of kynurenine, and it is not entirely clear whether the effects of kynurenine are direct or via these various metabolites. To further elucidate the mechanism by which KYN affects skeletal muscle we treated 22 month old male C57Bl/6 mice with two established metabolites of kynurenine; quinolinic acid (qa) and picolinic acid (pa). Qa was fed 1ppm for 8 weeks, and pa was fed 700ppm for 8 weeks. We then measured quadriceps femoris fiber size, weight, and muscle‐specific hydrogen peroxide levels at the end of the treatment period. In vivo QA and PA did not change skeletal muscle size, weight, or oxidative stress levels. We then pursued in vitro studies to evaluate other KYN metabolites that might contribute to muscle loss with aging. We treated C2C12 myoblasts with 10um of KYN, kynurenic acid, anthranillic acid, cinnabarinic acid, quinolinic acid, picolinic acid, nicotinic acid, and nicotinamide, and measured cell death and hydrogen peroxide levels. Cell death was increased by 10% in all groups compared to control (ANOVA P<.0001). Hydrogen peroxide was increased 2 fold in all groups compared to control (ANOVA P<.05). Cinnabarinic acid increased cell death by 25%, and increased hydrogen peroxide by 2.5 fold. These results suggest that some metabolites may be more potent than others, and these metabolites may be involved in age‐related muscle loss. Furthermore, the data suggest that enzymes downstream of IDO may be potential therapeutic targets for the prevention of sarcopenia and possibly other age‐associated conditions associated with KYN accumulation such as bone loss and neurodegeneration. Support or Funding Information NIA P01 AG036675