Peak aerobic power in humans (VO₂peak) is markedly affected by inspired O₂ tension (F_IO₂) but it remains unknown what factor plays a major role in the limitation of muscle peak VO₂ in hypoxia: PaO₂ or CaO₂? An answer to this classical question is given by studying the cardiac output (Cardio-green dye), leg blood flow (thermodilution), intra-arterial blood pressure and femoral arterial-to-venous differences in blood gases in humans performing exercise with a large (two-legged cycle ergometer exercise: BIKE) and a small (one-legged knee extension exercise: KNEE) muscle mass in normoxia, acute hypoxia (AH) (F_IO₂=0.105) and after 9 weeks of residence at 5260m (CH). Reducing the size of the active muscle mass blunts by 62% the effect of hypoxia on VO₂peak in AH and abolishes completely the effect of hypoxia on VO₂peak after altitude acclimatisation.

Acclimatisation improves BIKE peak exercise PaO₂ from 34 1 in AH to 45 1 mmHg in CH (P<0.05) and KNEE PaO₂ from 38 1 to 55 2 mmHg (P<0.05). Peak cardiac output and leg blood flow is reduced in hypoxia only during BIKE. Acute hypoxia results in reduction of systemic O₂ delivery (46 and 21%) and leg O₂ delivery (47 and 26%) during BIKE and KNEE, respectively, almost matching the corresponding reduction in VO₂peak. Altitude acclimatisation restors fully peak systemic and leg O₂ delivery in CH (2.69 0.27 and 1.28 0.11 l min^-1, respectively) to sea level values (2.65 0.15 and 1.16 0.11 l min^-1, respectively) during KNEE, but not during BIKE. During KNEE in CH leg oxygen delivery is similar to normoxia and, therefore also VO₂peak in spite of a PaO₂ 55 mmHg. Reducing the size of the active muscle mass improves pulmonary gas exchange during hypoxic exercise, attenuates the Bohr effect on oxygen uploading at the lungs and allows to preserve sea level convective O₂ transport to the active muscles. Thus, the altitude acclimatised human has potentially a similar exercising capacity as at sea level when the exercise model allows for an adequate oxygen delivery (blood flow x CaO₂), with only a minor role of PaO₂per se, when PaO₂ is > 55 mmHg.