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During exercise, fatigue is defined as a reversible reduction in force- or power-generating capacity and can be elicited by “central” and/or “peripheral” mechanisms. During skeletal muscle contractions, both aspects of fatigue may develop independent of alterations in convective O₂ delivery; however, reductions in O₂ supply exacerbate and increases attenuate the rate of accumulation. In this regard, peripheral fatigue development is mediated via the O₂-dependent rate of accumulation of metabolic by-products (e.g., inorganic phosphate) and their interference with excitation-contraction coupling within the myocyte. In contrast, the development of O₂-dependent central fatigue is elicited 1) by interference with the development of central command and/or 2) via inhibitory feedback on central motor drive secondary to the peripheral effects of low convective O₂ transport. Changes in convective O₂ delivery in the healthy …