We examined the effects of respiratory muscle work [inspiratory (W r-insp); expiratory (W r-exp)] and arterial oxygenation (SpO 2 ) on exerciseinduced locomotor muscle fatigue in patients with chronic obstructive pulmonary disease (COPD). Eight patients (FEV, 48 Ϯ 4%) performed constant-load cycling to exhaustion (Ctrl; 9.8 Ϯ 1.2 min). In subsequent trials, the identical exercise was repeated with 1) proportional assist ventilation ϩ heliox (PAV); 2) heliox (He:21% O 2); 3) 60% O 2 inspirate (hyperoxia); or 4) hyperoxic heliox mixture (He: 40% O 2). Five age-matched healthy control subjects performed Ctrl exercise at the same relative workload but for 14.7 min (Ϸbest COPD performance). Exercise-induced quadriceps fatigue was assessed via changes in quadriceps twitch force (Q tw,pot) from before to 10 min after exercise in response to supramaximal femoral nerve stimulation. During Ctrl, absolute workload (124 Ϯ 6 vs. 62 Ϯ 7 W), W r-insp (207 Ϯ 18 vs. 301 Ϯ 37 cmH 2O·s·min Ϫ1 ), Wr-exp (172 Ϯ 15 vs. 635 Ϯ 58 cmH 2O·s·min Ϫ1 ), and SpO 2 (96 Ϯ 1% vs. 87 Ϯ 3%) differed between control subjects and patients. Various interventions altered W r-insp, W r-exp, and SpO 2 from Ctrl (PAV: Ϫ55 Ϯ 5%, Ϫ21 Ϯ 7%, ϩ6 Ϯ 2%; He:21% O 2: Ϫ16 Ϯ 2%, Ϫ25 Ϯ 5%, ϩ4 Ϯ 1%; hyperoxia: Ϫ11 Ϯ 2%, Ϫ17 Ϯ 4%, ϩ16 Ϯ 4%; He:40% O 2: Ϫ22 Ϯ 2%, Ϫ27 Ϯ 6%, ϩ15 Ϯ 4%). Ten minutes after Ctrl exercise, Q tw,pot was reduced by 25 Ϯ 2% (P Ͻ 0.01) in all COPD and 2 Ϯ 1% (P ϭ 0.07) in healthy control subjects. In COPD, ⌬Q tw,pot was attenuated by onethird after each interventional trial; however, most of the exerciseinduced reductions in Q tw,pot remained. Our findings suggest that the high susceptibility to locomotor muscle fatigue in patients with COPD is in part attributable to insufficient O 2 transport as a consequence of exaggerated arterial hypoxemia and/or excessive respiratory muscle work but also support a critical role for the well-known altered intrinsic muscle characteristics in these patients.work of breathing; arterial oxygenation; blood flow; chronic obstructive pulmonary disease PATIENTS WITH chronic obstructive pulmonary disease (COPD) are characterized by endurance exercise intolerance, a characteristic consequence of the disease that impairs their capability for physical rehabilitation and contributes to their poor quality of life. Given the pathophysiological heterogeneity of COPD including various comorbidities (31), controversy exists about the prevailing determinants of the impaired capability for exercise in patients with COPD (2, 18, 54). The traditional view of perceived respiratory difficulty (dyspnea) as a critical factor restricting exercise is important and certainly plays a significant limiting role in many patients with COPD (34, 50). However, substantial exercise-induced locomotor muscle fatigue also occurs in many of these patients (34, 39 -41), and their susceptibility to peripheral muscle fatigue is greater than in age-matched healthy control subjects exercising at the same work rate (39, 40). Peripheral muscle fatigue ha...