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other·preclinical research, critical care, immunology, biomedical research·PMC10067504

Interleukin‐6 promotes skeletal muscle catabolism by activating tryptophan–indoleamine 2,3‐dioxygenase 1–kynurenine pathway during intra‐abdominal sepsis

Journal of Cachexia, Sarcopenia and Muscle · 11 authors, 3 centres

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TL;DR

This study combined human patient samples with a mouse sepsis model to investigate muscle wasting.

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The study combined an observational analysis of human intra-abdominal sepsis patients with mechanistic experiments in a mouse model of sepsis-induced muscle wasting. In patients, sepsis was associated with increased serum and muscle kynurenine levels and decreased tryptophan levels compared to non-sepsis controls. Blocking IL-6 with an antibody reduced IDO-1 expression and alleviated muscle loss. Conversely, administering kynurenine decreased muscle cross-sectional area even in IL-6-blocked septic mice. The authors conclude that IL-6 drives muscle catabolism via the IDO-1/kynurenine pathway.

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other

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preclinical research

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ORIGINAL PAPER

PMC10067504

Interleukin‐6 promotes skeletal muscle catabolism by activating tryptophan–indoleamine 2,3‐dioxygenase 1–kynurenine pathway during intra‐abdominal sepsis

Journal of Cachexia, Sarcopenia and Muscle

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ABSTRACT

Abstract Background Inflammatory cytokine interleukin‐6 (IL‐6) plays a pivotal role in skeletal muscle degradation after intra‐abdominal sepsis (IAS), with mechanism remained to be elucidated. Indoleamine 2,3‐dioxygenase 1 (IDO‐1), a key enzyme in converting tryptophan into kynurenine, could be activated by IL‐6, and kynurenine has been shown to be involved in muscle degradation. We hypothesized that IL‐6 could promote muscle degradation via tryptophan–IDO‐1–kynurenine pathway in IAS patients. Methods Serum and rectus abdominis (RA) were obtained from IAS or non‐IAS patients. Mouse model of IAS‐induced muscle wasting was generated by caecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection. IL‐6 signalling was blocked by anti‐mouse IL‐6 antibody (IL‐6‐AB), and the IDO‐1 pathway was blocked by navoximod. To elucidate the role of kynurenine in muscle mass and physiology, kynurenine was administered to IAS mice treated with IL‐6‐AB. Results Compared to non‐IAS patients, kynurenine levels in serum (+2.30‐fold vs. non‐IAS, P < 0.001) and RA (+3.11‐fold vs. non‐IAS, P < 0.001) were elevated, whereas tryptophan levels in serum (−53.65% vs. non‐IAS, P < 0.01) and RA (−61.39% vs. non‐IAS, P < 0.01) were decreased. Serum IL‐6 level of the IAS group was significantly higher compared to non‐IAS patients (+5.82‐fold vs. non‐IAS, P = 0.01), and muscle cross‐sectional area (MCSA) was markedly reduced compared to non‐IAS patients (−27.73% vs. non‐IAS, P < 0.01). In animal experiments, IDO‐1 expression was up‐regulated in the small intestine, colon and blood for CLP or LPS‐treated mice, and there was correlation ( R 2 = 0.66, P < 0.01) between serum and muscle kynurenine concentrations. Navoximod significantly mitigated IAS‐induced skeletal muscle loss according to MCSA analysis (+22.94% vs. CLP, P < 0.05; +23.71% vs. LPS, P < 0.01) and increased the phosphorylated AKT (+2.15‐fold vs. CLP, P < 0.01; +3.44‐fold vs. LPS, P < 0.01) and myosin heavy chain (+3.64‐fold vs. CLP, P < 0.01; +2.13‐fold vs. LPS, P < 0.01) protein expression in myocytes. In the presence of anti‐IL‐6 antibody, a significantly decreased IDO‐1 expression was observed in the small intestine, colon and blood in CLP or LPS mice (all P < 0.01), whereas the decrease of MCSA was alleviated (+37.43% vs. CLP + IgG, P < 0.001; +30.72% vs. LPS + IgG, P < 0.001). In contrast, additional supplementation of kynurenine decreased the MCSA in septic mice treated with IL‐6‐AB (both P < 0.01). Conclusions This study provided novel insights into the tryptophan–IDO‐1–kynurenine‐dependent mechanisms that underlie inflammatory cytokine‐induced skeletal muscle catabolism during intra‐abdominal sepsis.

CITATION EXPORT

Tingbin Xie, Tengfei Lv, Tenghui Zhang et al.. Interleukin‐6 promotes skeletal muscle catabolism by activating tryptophan–indoleamine 2,3‐dioxygenase 1–kynurenine pathway during intra‐abdominal sepsis. Journal of Cachexia, Sarcopenia and Muscle. (2023). https://doi.org/10.1002/jcsm.13193

AUTHORS

11 · 3 CENTRES

Tingbin Xie, Tengfei Lv, Tenghui Zhang, Dengyu Feng, Feng Zhu, Yi Xu, Liang Zhang, Lili Gu, Zhen Guo, Chao Ding, Jianfeng Gong

1 Department of General Surgery Jinling Hospital, Medical School of Nanjing University Nanjing China
2 Department of Gastrointestinal Surgery Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College Jiangsu, P.R. China
3 Department of General Surgery Drum Tower Hospital, Medical School of Nanjing University Nanjing China