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When freed from central cardiorespiratory limitations, healthy human skeletal muscle has exhibited a significant metabolic reserve. We studied the existence of this reserve in 10 severely compromised (FEV₁ = 0.97 ± SE 0.01) patients with chronic obstructive pulmonary disease (COPD). To manipulate O₂ supply and O₂ demand in locomotor and respiratory muscles, subjects performed both maximal conventional two-legged cycle ergometry (large muscle mass) and single-leg knee extensor exercise (KE, small muscle mass) while breathing room air (RA), 100% O₂, and 79% helium + 21% O₂ (HeO₂). With each gas mixture, peak ventilation, peak heart rate, and perceived breathlessness were lower in KE than cycle exercise (p < 0.05). Arterial O₂ saturation and maximal work capacity increased in both exercise modalities while subjects breathed 100% O₂ (work: + 10% bike, + 25% KE, p < 0.05). HeO₂ …