At low power output exercise (below lactate threshold), the oxygen uptake increases linearly with power output, but at high power output exercise (above lactate threshold) some additional oxygen consumption causes a non-linearity in the overall VO₂ (oxygen uptake rate)–power output relationship. The functional significance of this phenomenon for human exercise tolerance is very important, but the mechanisms underlying it remain unknown. In the present work, a computer model of oxidative phosphorylation in intact skeletal muscle developed previously is used to examine the background of this relationship in different modes of exercise. Our simulations demonstrate that the non-linearity in the VO₂–power output relationship and the difference in the magnitude of this non-linearity between incremental exercise mode and square-wave exercise mode (constant power output exercise) can be generated by introducing into the model some hypothetical factor F (group of associated factors) that accumulate(s) in time during exercise. The performed computer simulations, based on this assumption, give proper time courses of changes in VO₂ and [PCr] after an onset of work of different intensities, including the slow component in VO₂, well matching the experimental results. Moreover, if it is assumed that the exercise terminates because of fatigue when the amount/intensity of F exceed some threshold value, the model allows the generation of a proper shape of the well-known power-duration curve. This fact suggests that the phenomenon of the non-linarity of the VO₂–power output relationship and the magnitude of this non-linearity in different modes of exercise is determined by some factor(s) responsible for muscle fatigue.