Determinants of maximal oxygen consumption.

This article lays out the determinants of maximal O 2 consumption (VO 2 max) achieved during high intensity endurance exercise. It is not a traditional topical review but rather an educational essay that intertwines chance observations made during an unrelated research project with a subsequent program of stepwise thought, analysis and experimentation to reveal how O 2 is delivered to and used by the mitochondria. The centerpiece is the recognition that O 2 is delivered by an inter-dependent system of transport components functioning as a "bucket brigade", made up of the lungs, heart, blood and circulation, and the muscles themselves, each of which affects O 2 transport by similar amounts as they change. There is thus no single "limiting factor" to VO 2 max. Moreover, each component is shown to quantitatively affect the performance of the others. Mitochondrial respiration is integrated into the O 2 transport system analysis to reveal its separate contribution to VO 2 max, and to show that mitochondrial PO 2 at VO 2 max must be extremely low. Clinical application of the O 2 transport systems analysis is described to separate central cardiopulmonary from peripheral tissue contributions to exercise limitation, illustrated by a study of patients with COPD. Finally, a short discussion of why muscles operating maximally must endure an almost anoxic state is offered. The hope is that in sum, both the increased understanding of O 2 transport and the scientific approach to achieving that understanding described in the review can serve as a model for solving other complex problems going forward.