Fiber atrophy, oxidative stress, and oxidative fiber reduction are the attributes of different phenotypes in chronic obstructive pulmonary disease patients

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.