Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection

Copeland, E. N.; Whitley, K. C.; Watson, C. J.; Baranowski, B. J.; Kurgan, N.; MacNeil, A. J.; MacPherson, R. E.; Fajardo, V. A.; Allison, D. J.

doi:10.1101/2022.01.14.476359

bioRxiv · 10.1101/2022.01.14.476359

Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection

Copeland, E. N.·Whitley, K. C.·Watson, C. J.·Baranowski, B. J.·Kurgan, N.·MacNeil, A. J.·MacPherson, R. E.·Fajardo, V. A.·Allison, D. J.

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Abstract

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. While the effect of regular exercise has been studied, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviors in approximately 25% of patients with DMD, possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of Duchenne muscular dystrophy (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 KYNA and KYNA:KYN ratio compared with their respective wild-type (WT) controls. Moreover, only D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of their cages during a novel object recognition test when compared with WT. Along with this, we found that muscles from D2 mdx mice had less peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and kynurenine amino transferase-1 enzyme content as well as elevated expression of inflammatory cytokines compared with WT muscles. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.

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Copeland, E. N., Whitley, K. C., Watson, C. J., Baranowski, B. J., Kurgan, N., MacNeil, A. J., MacPherson, R. E., Fajardo, V. A., Allison, D. J.. 2022-01-16. Kynurenine metabolism is altered in mdx mice: a potential muscle to brain connection. https://doi.org/10.1101/2022.01.14.476359

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