Central regulation of skeletal muscle recruitment explains the reduced maximal cardiac output during exercise in hypoxia

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Abstract
Calbet JAL, Boushel R, Radegran G, Sondergaard H, Wagner PD, and Saltin B. Determinants of maximal oxygen uptake in severe acute hypoxia. Am J Physiol Regul Integr Comp Physiol 284: R291 R303, 2003. —To unravel the mechanisms by which maximal oxygen uptake (V̇o2 max) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O2 in N2 (hypoxia, ∼5,300 m above sea level). With hypoxia, exercise PaO2 dropped to 31–34 mmHg and arterial O2 content (CaO2) was reduced by 35% ( P < 0.001). Forty-one percent of the reduction in CaO2 was explained by the lower inspired O2 pressure (PiO2) in hypoxia, whereas the rest was due to the impairment of the pulmonary gas exchange, as reflected by the higher alveolar-arterial O2 difference in hypoxia ( P < 0.05). Hypoxia caused a 47% decrease in V̇o2 max (a greater fall than accountable by reduced CaO2). Peak cardiac output decreased by 17% ( P < 0.01), due to equal reductions in both peak heart rate and stroke volume ( P < 0.05). Peak leg blood flow was also lower (by 22%, P < 0.01). Consequently, systemic and leg O2 delivery were reduced by 43 and 47%, respectively, with hypoxia ( P < 0.001) correlating closely with V̇o2 max ( r = 0.98, P < 0.001). Therefore, three main mechanisms account for the reduction of V̇o2 max in severe acute hypoxia: 1 ) reduction of PiO2, 2 ) impairment of pulmonary gas exchange, and 3 ) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in V̇o2 max. Calbet JAL, Boushel R, Radegran G, Sondergaard H, Wagner PD, and Saltin B. Why is the V̇o2 max after altitude acclimatization still reduced despite normalization of arterial O2 content? Am J Physiol Regul Integr Comp Physiol 284: R304-R316, 2003.—Acute hypoxia (AH) reduces maximal O2 consumption (V̇o2 max), but after acclimatization, and despite increases in both hemoglobin concentration and arterial O2 saturation that can normalize arterial O2 concentration ([O2]), V̇o2 max remains low. To determine why, seven lowlanders were studied at V̇o2 max (cycle ergometry) at sea level (SL), after 9–10 wk at 5,260 m [chronic hypoxia (CH)], and 6 mo later at SL in AH (FiO2 = 0.105) equivalent to 5,260 m. Pulmonary and leg indexes of O2 transport were measured in each condition. Both cardiac output and leg blood flow were reduced by ∼15% in both AH and CH ( P < 0.05). At maximal exercise, arterial [O2] in AH was 31% lower than at SL ( P < 0.05), whereas in CH it was the same as at SL due to both polycythemia and hyperventilation. O2 extraction by the legs, however, remained at SL values in both AH and CH. Although at both SL and in AH, 76% of the cardiac output perfused the legs, in CH the legs received only 67%. Pulmonary V̇o2 max (4.1 ± 0.3 l/min at SL) fell to 2.2 ± 0.1 l/min in AH ( P < 0.05) and was only 2.4 ± 0.2 l/min in CH ( P < 0.05). These data suggest that the failure to recover V̇o2 max after acclimatization despite normalization of arterial [O2] is explained by two circulatory effects of altitude: 1 ) failure of cardiac output to normalize and 2 ) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH. To the Editor : The findings of Calbet and colleagues in this ([2][1], [3][2]) and another journal ([4][3]) are more consistent with a physiological model in which the brain regulates exercise performance by altering the number of motor units that are recruited under different conditions ([6][4], [7][5], [14][6], [15][7], [21][8]), rather than with the traditional model that the authors prefer and that posits that exercise performance is determined by the rate of oxygen delivery to the exercising muscles ([9][9]–[11][10], [18][11]–[20][12]). The authors studied cardiovascular and respiratory function in healthy lowlanders of both genders during maximum exercise 1 ) in acute hypoxia at sea level ([2][1]) and 2 ) at altitude after a period of 9–10 wk of altitude acclimatization ([3][2]), which increased blood hemoglobin content and hence the potential oxygen delivery to both heart and skeletal muscle at any given cardiac output ([4][3]). In addition, the acute effect of increasing the inspired oxygen fraction at the point of exhaustion was also studied. Their key findings were the following. ### Key finding 1. Peak cardiac output was reduced in subjects exposed either acutely or chronically to hypoxia, as previously shown ([23][13]–[25][14], [27][15], [28][16]). This reduction was due to decreases in both heart rate and stroke volume. ### Key finding 2. However, under all conditions of hypoxia, cardiac output (2, 3, Fig. 3 A ), heart rate (2, Fig. 3 E ; 3, Fig. 3 C ), and stroke volume (2, Fig. 3C; 3, Fig. 3 E ) were entirely appropriate for the work rates at which they were measured. ### Key finding 3. Cardiac output increased marginally with acclimatization to chronic hypoxia (3, Fig. 3 A ) but was still substantially below the maximum value achieved in normoxia. ### Key finding 4. The increase in cardiac output during maximum exercise in hypoxia after altitude acclimatization was due to an increase in stroke volume, whereas heart rate was reduced (3, Fig. 3, E and C ). ### Key finding 5. Peak work rate did not increase significantly after altitude acclimatization (Ref. [3][2], Table 1), although measured O2 delivery to the exercising muscles increased by 40% (∼800 ml O2/min) (3, Fig. 4 C ), two-leg oxygen consumption (V̇o2) by ∼550 ml/min (3, Fig. 4 E ), whereas pulmonary V̇o2 appears to have increased by only ∼280 ml/min (3, [Fig. 2 D ][17]). ### Key finding 6. The substantially reduced exercise performance...