The Mediating Role of Kynurenine Pathway Metabolites on the Relationship Between Inflammation and Muscle Mass in Oldest-Old Men

Abstract

Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ± 4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [n = 305] with interleukin [IL-6, IL-1β, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%-92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se.

Keywords: Biomarkers; C-reactive protein; D3-creatine; Sarcopenia.

Figure 1.

Flow diagram of the study sample.

Figure 2.

Path diagram of mediation model.

Figure 3.

Forest plot displaying the results for the total effect, natural direct effect, and natural indirect effect from the mediation model. 3-hydroxyanthranilic acid (3-HAA), 3-hydroxykynurenine (3-HK), anthranilic acid (AA), kynurenic acid (KA), kynurenine (KYN), neopterin (NEO), nicotinamide (NAM), picolinic acid (PIC), quinolinic acid (QA), tryptophan (TRP), xanthurenic acid (XA), HKr ratio, ratio of 3-HK to the sum of KA, AA, XA, and 3-HAA.

Figure 4.

Summary of KP metabolites mediating the detrimental effect of inflammation on D₃-creatine (D₃Cr) muscle mass and proposed mechanism. Description: Chronic activation of the immune system in response to macromolecular and organelle damage, as well as the metabolic derangements that occur with aging, leads to an overactivation and likely dysregulation of IDO. This overstimulation of IDO drives the metabolic flux of TRP through the KP leading to the depletion of TRP and concomitant increases in levels of KYN (ie, increases in KYN/TRP) and the ensuing buildup of other catabolic metabolites along the KP such as 3-HK and QA, thus altering the ratios of neuro- and myo-toxic KP metabolites (highlighted in orange) to more neuro- and myo-protective (ie, 3-HK/XA and NAM/QA). 3-HAA (highlighted in green) may serve as a feedback mechanism within the KP following activation of IDO by proinflammatory cytokines given its anti-inflammatory actions. IDO = indoleamine 2,3-dioxygenase; KP = kynurenine pathway.