Dept of Respiratory Medicine, National Institute for Health Research Respiratory Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College London, London, UK.
Eur Respir J. 2013 Jun;41(6):1275-83. doi: 10.1183/09031936.00098412. Epub 2012 Dec 20.
Reduced quadriceps endurance in chronic obstructive pulmonary disease (COPD) is associated with a predominance of type II glycolytic fibres over type I oxidative fibres (fibre shift) and reduced muscle energy stores. The molecular mechanisms responsible for this remain unknown. We hypothesised that expression of known regulators of type I fibres and energy production in quadriceps muscle would differ in COPD patients with and without fibre shift. We measured lung function, physical activity, exercise performance, quadriceps strength and endurance (nonvolitionally) in 38 Global Initiative for Chronic Obstructive Lung Disease stage I-IV COPD patients and 23 healthy age-matched controls. Participants underwent a quadriceps biopsy: type I and II fibre proportions were determined using immunohistochemistry and fibre shift defined using published reference ranges. Calcineurin A, phosphorylated AMP kinase (phospho-AMPK)-α, protein kinase A-α catalytic subunits, modulators of calcineurin activity and calmodulin, 14-3-3 proteins were measured by Western blotting, and myocyte-enriched calcineurin-interacting protein-1 mRNA measured by quantitative PCR. Downstream, nuclear myocyte enhancer factor-2 capable of DNA binding was quantified by transcription factor ELISA. Unexpectedly, calcineurin expression was higher, while phospho-AMPK was lower, in COPD patients with fibre shift compared to COPD patients without fibre shift. Phospho-AMPK levels correlated with quadriceps endurance in patients. Reduced phospho-AMPK may contribute to reduced quadriceps oxidative capacity and endurance in COPD.
慢性阻塞性肺疾病（COPD）患者的股四头肌耐力降低与 II 型糖酵解纤维相对于 I 型氧化纤维（纤维转移）的优势以及肌肉能量储存减少有关。导致这种情况的分子机制尚不清楚。我们假设，股四头肌中已知的 I 型纤维和能量产生调节剂的表达在 COPD 患者中存在纤维转移和不存在纤维转移的情况下会有所不同。我们测量了 38 名 GOLD 分期 I-IV 期 COPD 患者和 23 名年龄匹配的健康对照者的肺功能、体力活动、运动表现、股四头肌力量和耐力（非自愿性）。参与者接受了股四头肌活检：使用免疫组织化学测定 I 型和 II 型纤维比例，并使用已发表的参考范围定义纤维转移。通过 Western blot 测定钙调神经磷酸酶 A、磷酸化 AMP 激酶（磷酸化 AMPK）-α、蛋白激酶 A-α催化亚基、钙调神经磷酸酶活性调节剂和钙调蛋白、14-3-3 蛋白，通过定量 PCR 测定肌细胞丰富的钙调神经磷酸酶相互作用蛋白-1 mRNA。通过转录因子 ELISA 定量核肌细胞增强因子-2 能够与 DNA 结合。出乎意料的是，与无纤维转移的 COPD 患者相比，有纤维转移的 COPD 患者的钙调神经磷酸酶表达更高，而磷酸化 AMPK 更低。磷酸化 AMPK 水平与患者的股四头肌耐力相关。磷酸化 AMPK 减少可能导致 COPD 患者股四头肌氧化能力和耐力降低。
