Kynurenines link chronic inflammation to functional decline and physical frailty.
Adult
Aged
Aged, 80 and over
Animals
Arginine
/ metabolism
Chronic Disease
Cytokines
/ blood
Disease Models, Animal
Female
Frail Elderly
Humans
Inflammation
/ metabolism
Interleukin-10
/ genetics
Kynurenine
/ blood
Male
Mice, Inbred C57BL
Middle Aged
Neuromuscular Junction
/ metabolism
Serotonin
/ blood
Tryptophan
/ blood
Walking Speed
Young Adult
Aging
Cytokines
Inflammation
Neurodegeneration
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
20 08 2020
20 08 2020
Historique:
received:
03
01
2020
accepted:
15
07
2020
entrez:
21
8
2020
pubmed:
21
8
2020
medline:
12
6
2021
Statut:
epublish
Résumé
Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.
Identifiants
pubmed: 32814718
pii: 136091
doi: 10.1172/jci.insight.136091
pmc: PMC7455140
doi:
pii:
Substances chimiques
Cytokines
0
IL10 protein, mouse
0
Interleukin-10
130068-27-8
Serotonin
333DO1RDJY
Kynurenine
343-65-7
Tryptophan
8DUH1N11BX
Arginine
94ZLA3W45F
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIA NIH HHS
ID : K08 AG058483
Pays : United States
Organisme : NIA NIH HHS
ID : K23 AG035005
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG028747
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG021334
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR071618
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG046441
Pays : United States
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