The present study tested whether, during moderate exercise, 1) the dynamic responses of ADP and changes in free energy of ATP hydrolysis (delta GATP) were similar to those of phosphocreatine [PCr; as would be expected for a simple controller of muscle respiration (QO2)] and 2) the rise in pulmonary O2 uptake (VO2) during cycle exercise would reflect the rise in muscle QO2 indicated by the calf PCr kinetics. The responses of PCr, Pi, ADP, and delta GATP were measured from the calf in five subjects during supine treadle exercise using 31P-magnetic resonance spectroscopy and compared with those for VO2, measured breath by breath during upright cycle exercise. The time constants for delta GATP [24.2 +/- 14.2 (SE) s] were not significantly different from those for PCr (26.3 +/- 17.3 s) and Pi (30.7 +/- 22.5 s) (P > 0.05). The time constants for phase 2 VO2 (29.9 +/- 16.8 s) were also similar to those of PCr. In contrast, the dynamics of ADP were distorted from those of PCr due to dynamic changes in pH. These results are consistent with mechanisms of respiratory control that feature substrate control by PCr or thermodynamic control through changes in delta GATP. However, these results are not consistent with substrate control by ADP in a simple fashion. Furthermore, the similarity of time constants for phase 2 VO2 and muscle PCr suggests that phase 2 VO2 kinetics reflect those of muscle QO2 in healthy subjects during moderate exercise.