INSERM U-1046, CHRU Montpellier, Department of Clinical Physiology, University of Montpellier I and II, Montpellier, France;
J Appl Physiol (1985). 2013 Dec;115(12):1796-805. doi: 10.1152/japplphysiol.00778.2013. Epub 2013 Oct 17.
Peripheral muscle dysfunction, associated with reductions in fiber cross-sectional area (CSA) and in type I fibers, is a key outcome in chronic obstructive pulmonary disease (COPD). However, COPD peripheral muscle function and structure show great heterogeneity, overlapping those in sedentary healthy subjects (SHS). While discrepancies in the link between muscle structure and phenotype remain unexplained, we tested whether the fiber CSA and the type I fiber reductions were the attributes of different phenotypes of the disease, using unsupervised clustering method and post hoc validation. Principal component analysis performed on functional and histomorphological parameters in 64 COPD patients {forced expiratory volume in 1 s (FEV1) = 42.0 [30.0-58.5]% predicted} and 27 SHS (FEV1 = 105.0 [95.0-114.0]% predicted) revealed two COPD clusters with distinct peripheral muscle dysfunctions. These two clusters had different type I fiber proportion (26.0 ± 14.0% vs. 39.8 ± 12.6%; P < 0.05), and fiber CSA (3,731 ± 1,233 vs. 5,657 ± 1,098 μm(2); P < 0.05). The "atrophic" cluster showed an increase in muscle protein carbonylation (131.5 [83.6-200.3] vs. 83.0 [68.3-105.1]; P < 0.05). Then, COPD patients underwent pulmonary rehabilitation. If the higher risk of exacerbations in the "atrophic" cluster did not reach statistical significance after adjustment for FEV1 (hazard ratio: 2.43; P = 0.11, n = 54), the improvement of VO2sl after training was greater than in the nonatrophic cluster (+24 ± 16% vs. +6 ± 13%; P < 0.01). Last, their age was similar (60.4 ± 8.8 vs. 60.8 ± 9.0 yr; P = 0.87), suggesting a different time course of the disease. We identified and validated two phenotypes of COPD patients showing different muscle histomorphology and level of oxidative stress. Thus our study demonstrates that the muscle heterogeneity is the translation of different phenotypes of the disease.
外周肌肉功能障碍与纤维横截面积（CSA）和 I 型纤维减少有关，是慢性阻塞性肺疾病（COPD）的一个关键结果。然而，COPD 外周肌肉功能和结构表现出很大的异质性，与久坐的健康受试者（SHS）重叠。尽管肌肉结构与表型之间的联系仍存在差异，但我们使用无监督聚类方法和事后验证来测试纤维 CSA 和 I 型纤维减少是否是疾病不同表型的特征。对 64 名 COPD 患者[第 1 秒用力呼气量（FEV1）= 42.0[30.0-58.5]%预计值]和 27 名 SHS（FEV1 = 105.0[95.0-114.0]%预计值]的功能和组织形态学参数进行主成分分析，揭示了两个具有不同外周肌肉功能障碍的 COPD 聚类。这两个聚类具有不同的 I 型纤维比例（26.0±14.0%与 39.8±12.6%；P<0.05）和纤维 CSA（3731±1233 与 5657±1098 μm2；P<0.05）。“萎缩”聚类显示肌肉蛋白羰基化增加（131.5[83.6-200.3]与 83.0[68.3-105.1]；P<0.05）。然后，COPD 患者接受了肺康复治疗。如果在调整 FEV1 后，“萎缩”聚类中更高的恶化风险没有达到统计学意义（危险比：2.43；P=0.11，n=54），那么训练后 VO2sl 的改善大于非萎缩聚类（+24±16%与+6±13%；P<0.01）。最后，他们的年龄相似（60.4±8.8 与 60.8±9.0 岁；P=0.87），提示疾病的不同进程。我们确定并验证了 COPD 患者的两种表型，它们表现出不同的肌肉组织形态学和氧化应激水平。因此，我们的研究表明，肌肉异质性是疾病不同表型的翻译。
