Chronic aryl hydrocarbon receptor activity phenocopies smoking-induced skeletal muscle impairment.
Chronic aryl hydrocarbon receptor activity phenocopies smoking-induced skeletal muscle impairment.
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DOI：
10.1002/jcsm.12826
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Hepple RT
中科院分区：
文献类型：
--
作者：
Thome T;Miguez K;Willms AJ;Burke SK;Chandran V;de Souza AR;Fitzgerald LF;Baglole C;Anagnostou ME;Bourbeau J;Jagoe RT;Morais JA;Goddard Y;Taivassalo T;Ryan TE;Hepple RT
慢性阻塞性肺病（COPD）患者表现出骨骼肌萎缩、去神经支配和线粒体氧化能力降低。虽然慢性烟草烟雾暴露与COPD肌肉损伤有关，但所涉及的机制尚不明确。芳香烃受体（AHR）是一种配体激活的转录因子，可通过多种外源配体（包括烟草烟雾）激活解毒途径。虽然短暂的AHR激活是适应性的，但慢性激活可能是有毒的。在此基础上，我们测试了慢性烟雾诱导的AHR激活会导致不良肌肉影响的假设。我们使用临床患者肌肉样本以及体外（C2C12肌管）和体内模型（小鼠）进行基因表达、线粒体功能、肌肉和神经肌肉接头形态学以及遗传操作（腺相关病毒介导的基因转移）。小鼠暴露于烟草烟雾16周后，肌肉萎缩，神经肌肉接头变性，氧化能力降低。同样，烟雾暴露重新编程肌肉转录组，下调线粒体和神经肌肉接头基因。在小鼠和人类患者标本中，烟雾暴露增加了肌肉AHR信号传导。从机制上讲，在培养的肌管中的实验表明，烟雾冷凝物激活AHR，引起线粒体损伤，并诱导AHR依赖性肌管萎缩。最后，为了分离AHR活性的作用，在没有烟雾暴露的情况下表达组成型活性AHR突变体引起培养的肌管中的萎缩和线粒体损伤，以及小鼠中的肌肉萎缩和神经肌肉接头变性。这些结果表明，慢性AHR活动，发生在吸烟者，表型的萎缩，线粒体损伤，和神经肌肉接头变性所造成的慢性烟草烟雾暴露。
Chronic obstructive pulmonary disease (COPD) patients exhibit skeletal muscle atrophy, denervation, and reduced mitochondrial oxidative capacity. Whilst chronic tobacco smoke exposure is implicated in COPD muscle impairment, the mechanisms involved are ambiguous. The aryl hydrocarbon receptor (AHR) is a ligand‐activated transcription factor that activates detoxifying pathways with numerous exogenous ligands, including tobacco smoke. Whereas transient AHR activation is adaptive, chronic activation can be toxic. On this basis, we tested the hypothesis that chronic smoke‐induced AHR activation causes adverse muscle impact. We used clinical patient muscle samples, and in vitro (C2C12 myotubes) and in vivo models (mouse), to perform gene expression, mitochondrial function, muscle and neuromuscular junction morphology, and genetic manipulations (adeno‐associated virus‐mediated gene transfer). Sixteen weeks of tobacco smoke exposure in mice caused muscle atrophy, neuromuscular junction degeneration, and reduced oxidative capacity. Similarly, smoke exposure reprogrammed the muscle transcriptome, with down‐regulation of mitochondrial and neuromuscular junction genes. In mouse and human patient specimens, smoke exposure increased muscle AHR signalling. Mechanistically, experiments in cultured myotubes demonstrated that smoke condensate activated the AHR, caused mitochondrial impairments, and induced an AHR‐dependent myotube atrophy. Finally, to isolate the role of AHR activity, expression of a constitutively active AHR mutant without smoke exposure caused atrophy and mitochondrial impairments in cultured myotubes, and muscle atrophy and neuromuscular junction degeneration in mice. These results establish that chronic AHR activity, as occurs in smokers, phenocopies the atrophy, mitochondrial impairment, and neuromuscular junction degeneration caused by chronic tobacco smoke exposure.
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芳基烃受体（AHR）：外国和内源性信号的“传感器”的基本螺旋/环/螺旋（BHLH/PAS）家族的“先驱成员”。
影响因子：
13.6
作者：
Nebert DW
通讯作者：
Nebert DW
影响因子：
4.6
作者：
Berru, Fabian N.;Gray, Sarah E.;Ryan, Terence E.
通讯作者：
Ryan, Terence E.
影响因子：
4.5
作者：
Brunnberg, Sara;Andersson, Patrik;Hanberg, Annika
通讯作者：
Hanberg, Annika
DOI：
10.1164/rccm.201410-1830pp
发表时间：
2015-03-15
影响因子：
24.7
作者：
Degens, Hans;Gayan-Ramirez, Ghislaine;van Hees, Hieronymus W. H.
通讯作者：
van Hees, Hieronymus W. H.
影响因子：
--
作者：
Bucher S;Le Guillou D;Allard J;Pinon G;Begriche K;Tête A;Sergent O;Lagadic-Gossmann D;Fromenty B
通讯作者：
Fromenty B