Exercise capacity and training response are limited in chronic obstructive pulmonary disease (COPD), but the extent to which this is related to altered skeletal muscle function is not fully understood. To test the hypothesis that muscle gene expression is altered in COPD, we performed needle biopsies from the vastus lateralis of six COPD patients and five sedentary age-matched healthy men, before and after 3 mo of exercise training. RNA was hybridized to Affymetrix U133A Genechip arrays. In addition, peak O(2) uptake and other functional parameters (e.g., 6-min walk) were measured before and after training. The 6-min walk test increased significantly following training in both groups (53.6 +/- 18.6 m in controls, P = 0.045; 37.1 +/- 6.7 m in COPD, P = 0.002), but peak O(2) uptake increased only in controls (19.4 +/- 4.5%, P = 0.011). Training significantly altered muscle gene expression in both groups, but the number of affected genes was lower in the COPD patients (231) compared with controls (573). Genes related to energy pathways had higher expression in trained controls. In contrast, oxidative stress, ubiquitin proteasome, and COX gene pathways had higher expression in trained COPD patients, and some genes (e.g., COX11, COX15, and MAPK-9) were upregulated by training only in COPD patients. We conclude that both COPD and control subjects demonstrated functional responses to training but with somewhat different patterns in muscle gene expression. The pathways that are uniquely induced by exercise in COPD (e.g., ubiquitin proteasome and COX) might indicate a greater degree of tissue stress (perhaps by altered O(2) and CO(2) dynamics) than in controls.