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2006). Moreover, cycling time to exhaustion was increased by 14% in these subjects. Within the context GPX4 of the above brief synopsis, here we address two questions. First, is the work of breathing higher during exercise in hypoxia? Second, and exercise performance are decreased with increasing altitude; does the work of breathing in hypoxia contribute to this limitation? There is a metabolic cost associated with the rise in ventilation and additional activity of respiratory muscles. In contrast, air density is reduced significantly at high altitudes, which should correspond to a reduction in airway resistance. This question was addressed in healthy but untrained men performing treadmill exercise in the following three conditions: (i) sea level; (ii) sea level breathing a hypoxic inspirate (fractional inspired O2, 15%); and (iii) at high altitude (3100 m; Thoden et al. 1969). For a given value of , the work of breathing was significantly higher at altitude compared with sea-level conditions of breathing ambient air or hypoxic air (Fig. 1). At higher levels of exercise intensity at altitude the work of breathing was 35�C40% greater compared with the same exercise at sea level. Beyond a of 65 l min?1 at high altitude, the work of breathing was significantly increased relative to sea-level exercise. It appears that the reduction in airway resistance at high altitude is offset by the increasing turbulent flow selleck compound produced by high flow rates. It should also be emphasized that performing heavy exercise in hypoxia and the increased ventilatory requirement will place the athlete EGFR inhibitor closer to the limits of the maximal flow volume loop. Intersection with the maximal loop or expiratory flow limitation causes additional respiratory muscle work by increasing flow resistance, distorting the chest wall and increasing end-expiratory lung volume. The rise in end-expiratory lung volume (or relative hyperinflation) causes the inspiratory muscles to operate at shorter than normal lengths, and therefore the ability to lower intrathoracic pressure is reduced and the elastic work of breathing is increased. Other studies have estimated the O2 cost of breathing during exercise at high altitude to be greater than at sea level. For example, during exercise at 5050 m the O2 cost can be as much as 24�C26% of (Cibella et al. 1999). In summary, the density of inspired gas at high altitude is reduced but the net effect is an overall increase in the work of breathing. Several groups have shown that exercise performed in acute hypoxic conditions significantly increases the rate of development of locomotor muscle fatigue relative to normoxic exercise. Human quadriceps muscle fatigability during isolated muscle exercise is greater in acute hypoxia compared with normoxia as expressed as a percentage reduction in twitch force (?27 versus?21%, P