小柯机器人

土耳其科奇大学Serkan Kir团队发现，EDA2R-NIK信号促进与癌症恶病质有关的肌肉萎缩。相关论文于2023年5月10日在线发表在《自然》杂志上。

研究人员在肌肉组织中的基因表达分析表明，在肿瘤小鼠和恶性肿瘤患者中，外切酶A2受体（EDA2）的上调。结果显示，EDA2信号的激活促进了骨骼肌的萎缩。用EDA2配体刺激原代肌管，通过诱导肌肉萎缩相关基因Atrogin1和MuRF1的表达，引发了明显的细胞萎缩。EDA-A2驱动的肌管萎缩涉及非经典NF?B途径的激活，并依赖于NFκB诱导激酶（NIK）的活性。EDA-A2的过量表达促进了小鼠的肌肉萎缩，而EDA2或肌肉NIK的缺失则保护了肿瘤小鼠的肌肉质量和功能丧失。肿瘤诱导的oncostatin M（OSM）上调了肌肉EDA2R的表达，而肌肉特异性oncostatin M受体（OSMR）基因敲除的小鼠对肿瘤诱导的肌肉萎缩有抵抗力。

这些结果表明，EDA2R-NIK信号以OSM-OSMR依赖的方式介导癌症相关的肌肉萎缩。因此，针对这些途径的治疗可能有利于预防肌肉萎缩。

据介绍，骨骼肌萎缩是恶病质综合征的一个标志，与癌症患者的生存率低和生活质量下降有关。肌肉萎缩包括过度的蛋白质分解和肌肉质量及力量的丧失。由于对驱动萎缩过程的机制仍不完全了解，目前还缺乏针对肌肉萎缩的有效疗法。

附：英文原文

Title: EDA2R–NIK signalling promotes muscle atrophy linked to cancer cachexia

Author: Bilgic, Sevval Nur, Domaniku, Aylin, Toledo, Batu, Agca, Samet, Weber, Bahar Z. C., Arabaci, Dilsad H., Ozornek, Zeynep, Lause, Pascale, Thissen, Jean-Paul, Loumaye, Audrey, Kir, Serkan

Issue&Volume: 2023-05-10

Abstract: Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer1. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength2. An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the non-canonical NFB pathway and was dependent on NFκB-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatinM (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatinM receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R–NIK signalling mediates cancer-associated muscle atrophy in an OSM–OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss.

DOI: 10.1038/s41586-023-06047-y

Source: https://www.nature.com/articles/s41586-023-06047-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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