Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection.
Animals
Brain
/ metabolism
Disease Models, Animal
Kynurenic Acid
/ metabolism
Kynurenine
/ metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Inbred mdx
Muscle, Skeletal
/ metabolism
Muscular Dystrophy, Duchenne
/ metabolism
Peroxisome Proliferator-Activated Receptors
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
KYNA
anxiety
mental health
muscular dystrophy
Journal
Experimental physiology
ISSN: 1469-445X
Titre abrégé: Exp Physiol
Pays: England
ID NLM: 9002940
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
15
02
2022
accepted:
26
07
2022
pubmed:
2
8
2022
medline:
9
9
2022
entrez:
1
8
2022
Statut:
ppublish
Résumé
What is the central question in this study? Promoting muscle health with regular aerobic exercise can improve mental health through a kynurenine metabolic pathway: do conditions of muscle disease such as muscular dystrophy negatively influence this pathway? What is the main finding and its importance? The DBA/2J mdx model of Duchenne muscular dystrophy exhibits altered kynurenine metabolism with less kynurenic acid and peroxisome proliferator-activated receptor-γ coactivator 1-α and higher levels of tumour necrosis factor α mRNA - results associated with anxiety-like behaviour. Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. However, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviours in approximately 25% of patients with Duchenne muscular dystrophy (DMD), possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of DMD. Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating kynurenic acid (KYNA) and lower KYNA:KYN ratio compared with their respective wild-type (WT) controls. While both C57 and D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of the arena during a novel object recognition test, this effect was more prominent in D2 mdx mice. Correlational analysis detected a significant negative association between KYNA:KYN levels and time spent in corners in D2 mice, but not C57 mice. In extensor digitorum longus muscles from D2 mdx mice, but not C57 mdx mice, we found lowered protein levels of peroxisome proliferator-activated receptor-γ coactivator 1-α and kynurenine amino transferase-1 enzyme when compared with WT. Furthermore, D2 mdx quadriceps muscles had the highest level of tumour necrosis factor α expression, which is suggestive of enhanced inflammation. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.
Substances chimiques
Peroxisome Proliferator-Activated Receptors
0
Tumor Necrosis Factor-alpha
0
Kynurenine
343-65-7
Kynurenic Acid
H030S2S85J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1029-1036Informations de copyright
© 2022 The Authors. Experimental Physiology © 2022 The Physiological Society.
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