Impaired Skeletal Muscle Kynurenine Metabolism in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Background: Loss of peripheral muscle oxidative phenotype, cognitive impairment, and depression are well-recognized systemic manifestations of chronic obstructive pulmonary disease (COPD). Kynurenine (KYN), known to be associated with disturbed mental health, can be metabolized in muscle by kynurenine aminotransferases (KAT) 1–4. These KATs are regulated by peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC1α). We hypothesize that impaired PGC1α signaling in COPD is associated with reduced muscle KAT expression and increased KYN plasma levels. Methods: Retrospective collected and metabolically phenotyped muscle tissue and blood obtained from 29 well-characterized COPD patients and 15 healthy controls were analyzed. KYN was measured in plasma and KAT1–4 expression and major constituents of PGC1α signaling were assessed in quadriceps muscle biopsies. Results: Circulating KYN levels were increased in COPD. Furthermore, both gene and protein expression levels of KAT4 were reduced in muscle tissue from COPD patients. Finally, in the whole group (even when controlled for airflow obstruction) and in each subgroup separately, KAT4 gene expression correlated significantly with constituents of the PGC1α signaling pathway. Conclusions: These data support our hypothesis that KYN plasma levels are elevated in COPD through impaired KYN clearance in muscle. Our findings show a pathway via which exercise training and/or nutritional modulation may improve physical and mental health in COPD patients.

Changes in Body Composition During Adjuvant FOLFOX Chemotherapy and Overall Survival in Non-Metastatic Colon Cancer

“…Smoking showed a strong influence on the natural history of chronic obstructive pulmonary disease (COPD) and smoking related COPD was a significant predictor of more visit to emergency room and hospital readmission in colon cancer patients treated with adjuvant chemotherapy [39,40]. Experimental evidences revealed that smoking could influence skeletal muscle depletion and some muscle metabolism might be impaired in COPD patients [41,42]. Based on these effects of smoking, we believe that the trajectory association among smoking, body composition changes, and chemotherapy tolerance in patients with colon cancer needs to be further investigated.…”

Effect of targeted nutrient supplementation on physical activity and health-related quality of life in COPD: study protocol for the randomised controlled NUTRECOVER trial

“…In muscle, kynurenine can also be metabolised and cleared by kynurenine aminotransferases that are regulated by PGC-1α. Interestingly, a recent study of our group showed reduced expression levels of these aminotransferases in skeletal muscle of patients with COPD, which might explain the elevated plasma kynurenine levels 27. Impairments in the kynurenine pathway have been linked to anxiety, depression and cognitive decline 28…”

“…The extrapulmonary manifestations in COPD are linked by the cross-talk between the gut–muscle–brain axis which includes the vagus nerve, gut hormone signalling, the immune system, serotonin and tryptophan metabolism and microbial metabolites such as short-chain fatty acids 25. All routes might be disturbed in patients with COPD, but especially serotonin and tryptophan metabolism has recently been shown to be impaired in patients with COPD leading to unfavourable higher kynurenine/tryptophan ratios in the circulation 26 27. By modulating tryptophan availability, the microbiota can regulate the kynurenine pathway decreasing plasma kynurenine levels.…”

“…Circulating KYN and KYN/tryptophan ratios are elevated compared with controls and is associated with disease severity,26 KYN clearance might be reduced in skeletal muscle tissue of patients with COPD due to reduced PPAR/PGC-1α-mediated KAT expression 27…”

Physical Exercise as Kynurenine Pathway Modulator in Chronic Diseases: Implications for Immune and Energy Homeostasis

“…Detailed functional and regulatory aspects of the KYN pathway have been reviewed elsewhere. 1 The KYN pathway is deregulated in various chronic diseases, such as different internal (eg, chronic obstructive pulmonary disease, 4 diabetes, 2 cancer 5 ) or neurological (eg, multiple sclerosis, 6 Alzheimer and Parkinson disease 7 ) disorders. When compared with healthy controls, most of these diseases show a persistent overactivation of the KYN pathway as indicated by elevated levels of KYN and the KYN/TRP ratio.…”