Cited by 739Tryptophan and brain disordersTreatment of Major DepressionStress Responses and Cortisol

Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression

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Agudelo, Leandro Z., Femenía, Teresa, Orhan, Funda, Porsmyr-Palmertz, Margareta, Goiny, Michel, Martinez-Redondo, Vicente, Correia, Jorge C., Izadi, Manizheh +10 more·2014·Cell

Abstract

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

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Crossref · 10.1016/j.cell.2014.07.051

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73 of 73 references verified0 citation errors · 0 not checkable

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  • Increased expression of muscle-specific PGC-1a1 in transgenic mice is associated with greater resilience to chronic stress and stress-induced CNS inflammation.

    “increased expression of muscle-specific PGC-1a1 in transgenic mice was associated with greater resilience to chronic stress and stress-induced CNS inflammation (Agudelo et al., 2014).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Agudelo et al., 2014

  • This shift in kynurenine metabolism can protect the brain from stress-induced depression.

    “This shift in kynurenine metabolism is able to protect the brain from stress-induced depression150.”

    From Exerkines in health, resilience and disease (2022) · cites this paper as [150]

  • Evidence is accumulating that factors released from non-neuronal tissue and delivered to the brain via the vasculature may have important roles in synaptic plasticity, memory function and mood regulation.

    “Evidence is now accumulating that factors released from non-neuronal tissue148–152 and delivered via the vasculature to the brain might have important roles in synaptic plasticity, memory function and mood regulation150.”

    From Exerkines in health, resilience and disease (2022) · cites this paper as [150]

  • In mice and humans, chronic aerobic training increases muscle expression of kynurenine aminotransferase, which facilitates conversion of kynurenine to kynurenic acid, a metabolite unable to cross the blood-brain barrier.

    “In both mice and humans, chronic aerobic training increases muscle expression of kynurenine aminotransferase, which facilitates conversion of kynurenine into kynurenic acid, a metabolite that is unable to cross the blood-brain barrier.”

    From Exerkines in health, resilience and disease (2022) · cites this paper as [150]

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Authors
Agudelo, L. Z., Femenía, T., Orhan, F., Porsmyr-Palmertz, M., Goiny, M., Martinez-Redondo, V., Correia, J. C., Izadi, M., Bhat, M., Schuppe-Koistinen, I., Pettersson, A. T., Ferreira, D. M. S., Krook, A., Barres, R., Zierath, J. R., Erhardt, S., Lindskog, M., & Ruas, J. L.
Affiliations
  • Karolinska Institutet (SE)
  • Science for Life Laboratory (SE)
Corresponding author
  • Lindskog, Maria
  • Ruas, Jorge L.
Venue
Cell
Publisher
Elsevier BV
Published
2014-09
Volume
159
Issue
1
Pages
33-45
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2117415152
Cited by
739
References
73
Citations by year
2026: 62 · 2025: 64 · 2024: 75 · 2023: 58 · 2022: 64 · 2021: 76 · 2020: 71 · 2019: 64 · 2018: 52 · 2017: 39 · 2016: 50 · 2015: 56 · 2014: 7
FWCI
15.50
Type
journal article
Language
en
Update notices
erratum (2015-01-15)
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
  • HAL (submittedVersion)
Funders
  • AstraZeneca
  • Novo Nordisk Fonden (NNF12OC1016062)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
kynurenine metabolism, kynurenic acid, kynurenine aminotransferase, skeletal muscle, exercise training, stress-induced depression, chronic mild stress, blood-brain barrier, transgenic mice, depression treatment
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Transaminases, Animals, Blood-Brain Barrier, Depression, Humans, Kynurenic Acid, Kynurenine, Physical Conditioning, Animal, Stress, Psychological, Transcription Factors, Muscle, Skeletal, Muscle Fibers, Skeletal, Gene Expression Profiling, PPAR alpha, Mice, Physical Conditioning, Human

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