Patel M S, Donaldson A V, Lewis A, Natanek S A, Lee J Y, Andersson Y M, Haji G, Jackson S G, Bolognese B J, Foley J P, Podolin P L, Bruijnzeel P L B, Hart N, Hopkinson N S, Man W D-C, Kemp P R, Polkey M I
NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust and Imperial College, UK; Imperial College London, UK.
Imperial College London, UK.
Respir Med. 2016 Apr;113:50-6. doi: 10.1016/j.rmed.2016.02.004. Epub 2016 Feb 15.
Klotho is an 'anti-ageing' hormone and transmembrane protein; Klotho deficient mice develop a similar ageing phenotype to smokers including emphysema and muscle wasting. The objective of this study was to evaluate skeletal muscle and circulating Klotho protein in smokers and COPD patients and to relate Klotho levels to relevant skeletal muscle parameters. We sought to validate our findings by undertaking complimentary murine studies.
Fat free mass, quadriceps strength and spirometry were measured in 87 participants (61 COPD, 13 'healthy smokers' and 13 never smoking controls) in whom serum and quadriceps Klotho protein levels were also measured. Immunohistochemistry was performed to demonstrate the location of Klotho protein in human skeletal muscle and in mouse skeletal muscle in which regeneration was occurring following injury induced by electroporation. In a separate study, gastrocnemius Klotho protein was measured in mice exposed to 77 weeks of smoke or sham air.
Quadriceps Klotho levels were lower in those currently smoking (p = 0.01), irrespective of spirometry, but were not lower in patients with COPD. A regression analysis identified current smoking status as the only independent variable associated with human quadriceps Klotho levels, an observation supported by the finding that smoke exposed mice had lower gastrocnemius Klotho levels than sham exposed mice (p = 0.005). Quadriceps Klotho levels related to local oxidative stress but were paradoxically higher in patients with established muscle wasting or weakness; the unexpected relationship with low fat free mass was the only independent association. Within locomotor muscle, Klotho localized to the plasma membrane and to centralized nuclei in humans and in mice with induced muscle damage. Serum Klotho had an independent association with quadriceps strength but did not relate to quadriceps Klotho levels or to spirometric parameters.
Klotho is expressed in skeletal muscle and levels are reduced by smoking. Despite this, quadriceps Klotho protein expression in those with established disease appears complex as levels were paradoxically elevated in COPD patients with established muscle wasting. Whilst serum Klotho levels were not reduced in smokers or COPD patients and were not associated with quadriceps Klotho protein, they did relate to quadriceps strength.
α-klotho是一种“抗衰老”激素和跨膜蛋白；α-klotho缺乏的小鼠会出现与吸烟者相似的衰老表型，包括肺气肿和肌肉萎缩。本研究的目的是评估吸烟者和慢性阻塞性肺疾病（COPD）患者的骨骼肌和循环α-klotho蛋白，并将α-klotho水平与相关骨骼肌参数联系起来。我们试图通过进行补充性的小鼠研究来验证我们的发现。
对87名参与者（61名COPD患者、13名“健康吸烟者”和13名从不吸烟的对照者）测量了去脂体重、股四头肌力量和肺活量，同时也测量了他们血清和股四头肌中的α-klotho蛋白水平。进行免疫组织化学以证明α-klotho蛋白在人类骨骼肌以及电穿孔诱导损伤后正在发生再生的小鼠骨骼肌中的定位。在另一项研究中，测量了暴露于烟雾77周或假空气的小鼠腓肠肌中的α-klotho蛋白。
目前吸烟的人股四头肌α-klotho水平较低（p = 0.01），与肺活量测定结果无关，但COPD患者的该水平并不低。回归分析确定当前吸烟状态是与人类股四头肌α-klotho水平相关的唯一独立变量，暴露于烟雾的小鼠腓肠肌α-klotho水平低于暴露于假空气的小鼠这一发现支持了该观察结果（p = 0.005）。股四头肌α-klotho水平与局部氧化应激有关，但在已出现肌肉萎缩或无力的患者中却反常地更高；与低去脂体重的意外关系是唯一的独立关联。在运动肌肉中，α-klotho定位于人类和诱导性肌肉损伤小鼠的质膜和集中的细胞核。血清α-klotho与股四头肌力量有独立关联，但与股四头肌α-klotho水平或肺活量测定参数无关。
α-klotho在骨骼肌中表达，且吸烟会使其水平降低。尽管如此，在患有既定疾病的人群中，股四头肌α-klotho蛋白表达似乎很复杂，因为在已出现肌肉萎缩的COPD患者中该水平反常升高。虽然吸烟者或COPD患者的血清α-klotho水平没有降低，且与股四头肌α-klotho蛋白无关，但它们确实与股四头肌力量有关。
