Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
J Cachexia Sarcopenia Muscle. 2024 Apr;15(2):646-659. doi: 10.1002/jcsm.13439. Epub 2024 Feb 9.
Accumulating evidence has demonstrated that chronic tobacco smoking directly contributes to skeletal muscle dysfunction independent of its pathological impact to the cardiorespiratory systems. The mechanisms underlying tobacco smoke toxicity in skeletal muscle are not fully resolved. In this study, the role of the aryl hydrocarbon receptor (AHR), a transcription factor known to be activated with tobacco smoke, was investigated.
AHR related gene (mRNA) expression was quantified in skeletal muscle from adult controls and patients with chronic obstructive pulmonary disease (COPD), as well as mice with and without cigarette smoke exposure. Utilizing both skeletal muscle-specific AHR knockout mice exposed to chronic repeated (5 days per week for 16 weeks) cigarette smoke and skeletal muscle-specific expression of a constitutively active mutant AHR in healthy mice, a battery of assessments interrogating muscle size, contractile function, mitochondrial energetics, and RNA sequencing were employed.
Skeletal muscle from COPD patients (N = 79, age = 67.0 ± 8.4 years) had higher levels of AHR (P = 0.0451) and CYP1B1 (P < 0.0001) compared to healthy adult controls (N = 16, age = 66.5 ± 6.5 years). Mice exposed to cigarette smoke displayed higher expression of Ahr (P = 0.008), Cyp1b1 (P < 0.0001), and Cyp1a1 (P < 0.0001) in skeletal muscle compared to air controls. Cigarette smoke exposure was found to impair skeletal muscle mitochondrial oxidative phosphorylation by ~50% in littermate controls (Treatment effect, P < 0.001), which was attenuated by deletion of the AHR in muscle in male (P = 0.001), but not female, mice (P = 0.37), indicating there are sex-dependent pathological effects of smoking-induced AHR activation in skeletal muscle. Viral mediated expression of a constitutively active mutant AHR in the muscle of healthy mice recapitulated the effects of cigarette smoking by decreasing muscle mitochondrial oxidative phosphorylation by ~40% (P = 0.003).
These findings provide evidence linking chronic AHR activation secondary to cigarette smoke exposure to skeletal muscle bioenergetic deficits in male, but not female, mice. AHR activation is a likely contributor to the decline in muscle oxidative capacity observed in smokers and AHR antagonism may provide a therapeutic avenue aimed to improve muscle function in COPD.
越来越多的证据表明，慢性吸烟直接导致骨骼肌功能障碍，而与心肺系统的病理影响无关。烟草烟雾毒性在骨骼肌中的作用机制尚未完全解决。在这项研究中，研究了芳香烃受体（AHR）的作用，AHR 是一种已知可被烟草烟雾激活的转录因子。
定量检测了成年对照组和慢性阻塞性肺疾病（COPD）患者以及接受和不接受香烟烟雾暴露的小鼠的骨骼肌中与 AHR 相关的基因（mRNA）表达。利用骨骼肌特异性 AHR 敲除小鼠和健康小鼠的骨骼肌特异性表达组成型活性突变 AHR，进行了一系列评估，包括肌肉大小、收缩功能、线粒体能量代谢和 RNA 测序。
COPD 患者（n=79，年龄=67.0±8.4 岁）的骨骼肌 AHR（P=0.0451）和 CYP1B1（P<0.0001）水平高于健康成年对照组（n=16，年龄=66.5±6.5 岁）。与空气对照组相比，香烟烟雾暴露的小鼠骨骼肌中 Ahr（P=0.008）、Cyp1b1（P<0.0001）和 Cyp1a1（P<0.0001）的表达更高。香烟烟雾暴露导致同窝对照的骨骼肌线粒体氧化磷酸化减少约 50%（处理效应，P<0.001），而肌肉 AHR 缺失可减轻雄性（P=0.001）但不能减轻雌性（P=0.37）小鼠的这种作用，表明吸烟诱导的 AHR 激活在骨骼肌中存在性别依赖性的病理作用。在健康小鼠的肌肉中，病毒介导的组成型活性突变 AHR 的表达可使肌肉线粒体氧化磷酸化减少约 40%（P=0.003），从而重现香烟烟雾的作用。
这些发现为慢性 AHR 激活与雄性而非雌性小鼠的骨骼肌生物能缺陷之间的联系提供了证据。AHR 激活可能是吸烟者肌肉氧化能力下降的原因之一，AHR 拮抗可能为改善 COPD 患者的肌肉功能提供一种治疗途径。
