Effect of exercise-induced arterial hypoxemia on quadriceps muscle fatigue in healthy humans

The effect of exercise-induced arterial hypoxemia (EIAH) on quadriceps muscle fatigue was assessed in 11 male endurance-trained subjects [peak O2 uptake (VO2 peak) = 56.4 +/- 2.8 ml x kg(-1) x min(-1); mean +/- SE]. Subjects exercised on a cycle ergometer at >or=90% VO2 peak) to exhaustion (13.2 +/- 0.8 min), during which time arterial O2 saturation (Sa(O2)) fell from 97.7 +/- 0.1% at rest to 91.9 +/- 0.9% (range 84-94%) at end exercise, primarily because of changes in blood pH (7.183 +/- 0.017) and body temperature (38.9 +/- 0.2 degrees C). On a separate occasion, subjects repeated the exercise, for the same duration and at the same power output as before, but breathed gas mixtures [inspired O2 fraction (Fi(O2)) = 0.25-0.31] that prevented EIAH (Sa(O2) = 97-99%). Quadriceps muscle fatigue was assessed via supramaximal paired magnetic stimuli of the femoral nerve (1-100 Hz). Immediately after exercise at Fi(O2) 0.21, the mean force response across 1-100 Hz decreased 33 +/- 5% compared with only 15 +/- 5% when EIAH was prevented (P < 0.05). In a subgroup of four less fit subjects, who showed minimal EIAH at Fi(O2) 0.21 (Sa(O2) = 95.3 +/- 0.7%), the decrease in evoked force was exacerbated by 35% (P < 0.05) in response to further desaturation induced via Fi(O2) 0.17 (Sa(O2) = 87.8 +/- 0.5%) for the same duration and intensity of exercise. We conclude that the arterial O2 desaturation that occurs in fit subjects during high-intensity exercise in normoxia (-6 +/- 1% DeltaSa(O2) from rest) contributes significantly toward quadriceps muscle fatigue via a peripheral mechanism.     

Effect of high-intensity hypoxic training on sea-level swimming performances.

The objective of this study was to test the hypothesis that high-intensity hypoxic training improves sea-level performances more than equivalent training in normoxia. Sixteen well-trained collegiate and Masters swimmers (10 women, 6 men) completed a 5-wk training program, consisting of three high-intensity training sessions in a flume and supplemental low- or moderate-intensity sessions in a pool each week. Subjects were matched for gender, performance level, and training history, and they were assigned to either hypoxic [Hypo; inspired O2 fraction (Fi(O(2))) = 15.3%, equivalent to a simulated altitude of 2,500 m] or normoxic (Norm; Fi(O(2)) = 20.9%) interval training in a randomized, double-blind, placebo-controlled design. All pool training occurred under Norm conditions. The primary performance measures were 100- and 400-m freestyle time trials. Laboratory outcomes included maximal O(2) uptake (Vo(2 max)), anaerobic capacity (accumulated O(2) deficit), and swimming economy. Significant (P = 0.02 and <0.001 for 100- and 400-m trials, respectively) improvements were found in performance on both the 100- [Norm: -0.7 s (95% confidence limits: +0.2 to -1.7 s), -1.2%; Hypo: -0.8 s (95% confidence limits: -0.1 to -1.5 s), -1.1%] and 400-m freestyle [Norm: -3.6 s (-1.8 to -5.5 s), -1.2%; Hypo: -5.3 s (-2.3 to -8.3 s), -1.7%]. There was no significant difference between groups for either distance (ANOVA interaction, P = 0.91 and 0.36 for 100- and 400-m trials, respectively). Vo(2 max) was improved significantly (Norm: 0.16 +/- 0.23 l/min, 6.4 +/-8.1%; Hypo: 0.11 +/- 0.18 l/min, 4.2 +/- 7.0%). There was no significant difference between groups (P = 0.58). We conclude that 5 wk of high-intensity training in a flume improves sea-level swimming performances and Vo(2 max) in well-trained swimmers, with no additive effect of hypoxic training.     

Muscle Na-K-pump and fatigue responses to progressive exercise in normoxia and hypoxia

To investigate the effects of hypoxia and incremental exercise on muscle contractility, membrane excitability, and maximal Na(+)-K(+)-ATPase activity, 10 untrained volunteers (age = 20 +/- 0.37 yr and weight = 80.0 +/- 3.54 kg; +/- SE) performed progressive cycle exercise to fatigue on two occasions: while breathing normal room air (Norm; Fi(O(2)) = 0.21) and while breathing a normobaric hypoxic gas mixture (Hypox; Fi(O(2)) = 0.14). Muscle samples extracted from the vastus lateralis before exercise and at fatigue were analyzed for maximal Na(+)-K(+)-ATPase (K(+)-stimulated 3-O-methylfluorescein phosphatase) activity in homogenates. A 32% reduction (P < 0.05) in Na(+)-K(+)-ATPase activity was observed (90.9 +/- 7.6 vs. 62.1 +/- 6.4 nmol.mg protein(-1).h(-1)) in Norm. At fatigue, the reductions in Hypox were not different (81 +/- 5.6 vs. 57.2 +/- 7.5 nmol.mg protein(-1).h(-1)) from Norm. Measurement of quadriceps neuromuscular function, assessed before and after exercise, indicated a generalized reduction (P < 0.05) in maximal voluntary contractile force (MVC) and in force elicited at all frequencies of stimulation (10, 20, 30, 50, and 100 Hz). In general, no differences were observed between Norm and Hypox. The properties of the compound action potential, amplitude, duration, and area, which represent the electromyographic response to a single, supramaximal stimulus, were not altered by exercise or oxygen condition when assessed both during and after the progressive cycle task. Progressive exercise, conducted in Hypox, results in an inhibition of Na(+)-K(+)-ATPase activity and reductions in MVC and force at different frequencies of stimulation; these results are not different from those observed with Norm. These changes occur in the absence of reductions in neuromuscular excitability.     

Effect of arterial oxygenation on quadriceps fatigability during isolated muscle exercise

The effect of various levels of oxygenation on quadriceps muscle fatigability during isolated muscle exercise was assessed in six male subjects. Twitch force (Q(tw)) was assessed using supramaximal magnetic femoral nerve stimulation. In experiment 1, maximal voluntary contraction (MVC) and Q(tw) of resting quadriceps muscle were measured in normoxia [inspired O(2) fraction (Fi(O(2))) = 0.21, percent arterial O(2) saturation (Sp(O(2))) = 98.4%, estimated arterial O(2) content (Ca(O(2))) = 20.8 ml/dl], acute hypoxia (Fi(O(2)) = 0.11, Sp(O(2)) = 74.6%, Ca(O(2)) = 15.7 ml/dl), and acute hyperoxia (Fi(O(2)) = 1.0, Sp(O(2)) = 100%, Ca(O(2)) = 22.6 ml/dl). No significant differences were found for MVC and Q(tw) among the three Fi(O(2)) levels. In experiment 2, the subjects performed three sets of nine, intermittent, isometric, unilateral, submaximal quadriceps contractions (62% MVC followed by 1 MVC in each set) while breathing each Fi(O(2)). Q(tw) was assessed before and after exercise, and myoelectrical activity of the vastus lateralis was obtained during exercise. The percent reduction of twitch force (potentiated Q(tw)) in hypoxia (-27.0%) was significantly (P < 0.05) greater than in normoxia (-21.4%) and hyperoxia (-19.9%), as were the changes in intratwitch measures of contractile properties. The increase in integrated electromyogram over the course of the nine contractions in hypoxia (15.4%) was higher (P < 0.05) than in normoxia (7.2%) or hyperoxia (6.7%). These results demonstrate that quadriceps muscle fatigability during isolated muscle exercise is exacerbated in acute hypoxia, and these effects are independent of the relative exercise intensity.     

Effect of acute severe hypoxia on peripheral fatigue and endurance capacity in healthy humans

We hypothesized that severe hypoxia limits exercise performance via decreased contractility of limb locomotor muscles. Nine male subjects [mean +/- SE maximum O(2) uptake (Vo(2 max)) = 56.5 +/- 2.7 ml x kg(-1) x min(-1)] cycled at > or =90% Vo(2 max) to exhaustion in normoxia [NORM-EXH; inspired O(2) fraction (Fi(O(2))) = 0.21, arterial O(2) saturation (Sp(O(2))) = 93 +/- 1%] and hypoxia (HYPOX-EXH; Fi(O(2)) = 0.13, Sp(O(2)) = 76 +/- 1%). The subjects also exercised in normoxia for a time equal to that achieved in hypoxia (NORM-CTRL; Sp(O(2)) = 96 +/- 1%). Quadriceps twitch force, in response to supramaximal single (nonpotentiated and potentiated 1 Hz) and paired magnetic stimuli of the femoral nerve (10-100 Hz), was assessed pre- and at 2.5, 35, and 70 min postexercise. Hypoxia exacerbated exercise-induced peripheral fatigue, as evidenced by a greater decrease in potentiated twitch force in HYPOX-EXH vs. NORM-CTRL (-39 +/- 4 vs. -24 +/- 3%, P < 0.01). Time to exhaustion was reduced by more than two-thirds in HYPOX-EXH vs. NORM-EXH (4.2 +/- 0.5 vs. 13.4 +/- 0.8 min, P < 0.01); however, peripheral fatigue was not different in HYPOX-EXH vs. NORM-EXH (-34 +/- 4 vs. -39 +/- 4%, P > 0.05). Blood lactate concentration and perceptions of limb discomfort were higher throughout HYPOX-EXH vs. NORM-CTRL but were not different at end-exercise in HYPOX-EXH vs. NORM-EXH. We conclude that severe hypoxia exacerbates peripheral fatigue of limb locomotor muscles and that this effect may contribute, in part, to the early termination of exercise.     

Effects of prior exercise and a low-carbohydrate diet on muscle sarcoplasmic reticulum function during cycling in women.

The effects of exercise and diet on sarcoplasmic reticulum Ca(2+)-cycling properties in female vastus lateralis muscle were investigated in two groups of women following four different conditions. The conditions were 4 days of a low-carbohydrate (Lo CHO) and glycogen-depleting exercise plus a Lo CHO diet (Ex + Lo CHO) (experiment 2) and 4 days of normal CHO (Norm CHO) and glycogen-depleting exercise plus Norm CHO (Ex + Norm CHO) (experiment 1). Peak aerobic power (Vo2peak)) was 38.1 +/- 1.4 (SE); n = 9 and 35.6 +/- 1.4 ml.kg(-1).min(-1); n = 9, respectively. Sarcoplasmic reticulum properties measured in vitro in homogenates (micromol.g protein(-1).min(-1)) indicated exercise-induced reductions (P < 0.05) in maximal Ca(2+)-ATPase activity (0 > 30, 60 min > fatigue), Ca(2+) uptake (0 > 30 > 60 min, fatigue), and Ca(2+) release, both phase 1 (0, 30 > 60 min, fatigue) and phase 2 (0 > 30, 60 min, fatigue; 30 min > fatigue) in Norm CHO. Exercise was without effect in altering the Hill slope (n(H)), defined as the slope of relationship between Ca(2+)-ATPase activity and Ca(2+) concentration. No differences were observed between Norm CHO and Ex+Norm CHO. Compared with Norm CHO, Lo CHO resulted in a lower (P < 0.05) Ca(2+) uptake, phase 1 Ca(2+) release (30 min), and n(H). Ex + Lo CHO resulted in a greater (P < 0.05) Ca(2+) uptake and n(H) compared with Lo CHO. The results demonstrate that Lo CHO alone can disrupt SR Ca(2+) cycling and that, with the exception of Ca(2+) release, a glycogen-depleting session of exercise before Lo CHO can reverse the effects.     

Effects of acute hypoxia on cerebral and muscle oxygenation during incremental exercise.

To determine if fatigue at maximal aerobic power output was associated with a critical decrease in cerebral oxygenation, 13 male cyclists performed incremental maximal exercise tests (25 W/min ramp) under normoxic (Norm: 21% Fi(O2)) and acute hypoxic (Hypox: 12% Fi(O2)) conditions. Near-infrared spectroscopy (NIRS) was used to monitor concentration (microM) changes of oxy- and deoxyhemoglobin (Delta[O2Hb], Delta[HHb]) in the left vastus lateralis muscle and frontal cerebral cortex. Changes in total Hb were calculated (Delta[THb] = Delta[O2Hb] + Delta[HHb]) and used as an index of change in regional blood volume. Repeated-measures ANOVA were performed across treatments and work rates (alpha = 0.05). During Norm, cerebral oxygenation rose between 25 and 75% peak power output {Power(peak); increased (inc) Delta[O2Hb], inc. Delta[HHb], inc. Delta[THb]}, but fell from 75 to 100% Power(peak) {decreased (dec) Delta[O2Hb], inc. Delta[HHb], no change Delta[THb]}. In contrast, during Hypox, cerebral oxygenation dropped progressively across all work rates (dec. Delta[O2Hb], inc. Delta[HHb]), whereas Delta[THb] again rose up to 75% Power(peak) and remained constant thereafter. Changes in cerebral oxygenation during Hypox were larger than Norm. In muscle, oxygenation decreased progressively throughout exercise in both Norm and Hypox (dec. Delta[O2Hb], inc. Delta [HHb], inc. Delta[THb]), although Delta[O2Hb] was unchanged between 75 and 100% Power peak. Changes in muscle oxygenation were also greater in Hypox compared with Norm. On the basis of these findings, it is unlikely that changes in cerebral oxygenation limit incremental exercise performance in normoxia, yet it is possible that such changes play a more pivotal role in hypoxia.     

Thyroid status and response to endothelin-1 in rat arterial vessels

We have previously reported that changes in thyroid status are associated with significant alterations in skeletal muscle blood flow during exercise and that changes in endothelium-dependent vasodilation may contribute to these blood flow abnormalities. The purpose of this study was to test the hypothesis that altered endothelium-dependent vasoconstriction is also associated with changes in thyroid status. To test this hypothesis, rats were rendered hypothyroid with propylthiouracil (Hypo, n = 14) or hyperthyroid with triiodothyronine (Hyper, n = 14) over approximately 3 mo. Treatment efficacy was confirmed by altered (P < 0.05) citrate synthase activity in several hindlimb skeletal muscles from Hypo and Hyper, compared with that in muscles from euthyroid rats (Eut, n = 12). Vascular rings were prepared from abdominal aortae, and responses to several vasoactive agents were determined in vitro. As found previously, maximal acetylcholine-induced vasorelaxation was modulated by thyroid status (Eut, 47 +/- 9; Hypo, 28 +/- 6; Hyper, 68 +/- 5%; P < 0.05). Contractile responses of vascular rings with intact endothelium to the endothelium-derived constrictor endothelin-1 (ET-1), however, were similar among groups across a range of ET-1 concentrations. In addition, maximal responses [Eut, 3.75 +/- 0.47; Hypo, 2.72 +/- 0.25; Hyper, 3.22 +/- 0.42 g; not significant (NS)] and sensitivities (Eut, 8.12 +/- 0.09; Hypo, 8.10 +/- 0.06; Hyper, 8.28 +/- 0.09 -log M; NS) to ET-1 were similar among groups. If these findings from the conduit-type abdominal aorta extend into resistance vasculature, it appears that changes in endothelium-dependent vasoconstriction do not contribute to skeletal muscle blood flow abnormalities associated with thyroid disease states.     

Inspiratory muscle work in acute hypoxia influences locomotor muscle fatigue and exercise performance of healthy humans

Our aim was to isolate the independent effects of 1) inspiratory muscle work (W(b)) and 2) arterial hypoxemia during heavy-intensity exercise in acute hypoxia on locomotor muscle fatigue. Eight cyclists exercised to exhaustion in hypoxia [inspired O(2) fraction (Fi(O(2))) = 0.15, arterial hemoglobin saturation (Sa(O(2))) = 81 +/- 1%; 8.6 +/- 0.5 min, 273 +/- 6 W; Hypoxia-control (Ctrl)] and at the same work rate and duration in normoxia (Sa(O(2)) = 95 +/- 1%; Normoxia-Ctrl). These trials were repeated, but with a 35-80% reduction in W(b) achieved via proportional assist ventilation (PAV). Quadriceps twitch force was assessed via magnetic femoral nerve stimulation before and 2 min after exercise. The isolated effects of W(b) in hypoxia on quadriceps fatigue, independent of reductions in Sa(O(2)), were revealed by comparing Hypoxia-Ctrl and Hypoxia-PAV at equal levels of Sa(O(2)) (P = 0.10). Immediately after hypoxic exercise potentiated twitch force of the quadriceps (Q(tw,pot)) decreased by 30 +/- 3% below preexercise baseline, and this reduction was attenuated by about one-third after PAV exercise (21 +/- 4%; P = 0.0007). This effect of W(b) on quadriceps fatigue occurred at exercise work rates during which, in normoxia, reducing W(b) had no significant effect on fatigue. The isolated effects of reduced Sa(O(2)) on quadriceps fatigue, independent of changes in W(b), were revealed by comparing Hypoxia-PAV and Normoxia-PAV at equal levels of W(b). Q(tw,pot) decreased by 15 +/- 2% below preexercise baseline after Normoxia-PAV, and this reduction was exacerbated by about one-third after Hypoxia-PAV (-22 +/- 3%; P = 0.034). We conclude that both arterial hypoxemia and W(b) contribute significantly to the rate of development of locomotor muscle fatigue during exercise in acute hypoxia; this occurs at work rates during which, in normoxia, W(b) has no effect on peripheral fatigue.     

Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia

Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O(2)) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-1alpha and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 +/- 6% and 67 +/- 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 +/- 2% of baseline in Hypo vs. 67 +/- 3% in Norm (P < 0.05). Improved postischemic right ventricular function in Hypo (93 +/- 2% and 96 +/- 2% of baseline) was observed with 95% O(2) or 21% O(2) in the perfusate, and it was not attenuated by glibenclamide (5 and 10 micromol/l) (86 +/- 4% and 106 +/- 6% recovery). HIF-1alpha mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K(+) channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts.     

Metabolic and sarcoplasmic reticulum Ca2+ cycling responses in human muscle 4 days following prolonged exercise

This study investigated the effects of prolonged exercise on muscle sarcoplasmic reticulum (SR) Ca2+ cycling properties and the metabolic responses with and without a session of exercise designed to reduce muscle glycogen reserves while on a normal carbohydrate (CHO) diet. Eight untrained males (VO(2peak) = 3.81 +/- 0.12 L/min, mean +/- SE) performed a standardized cycle-to-fatigue at 55% VO(2peak) while on a normal CHO diet (Norm CHO) and 4 days following prolonged exercise while on a normal CHO diet (Ex+Norm CHO). Compared to rest, exercise in Norm CHO to fatigue resulted in significant reductions (p < 0.05) in Ca2+ uptake (3.17 +/- 0.21 vs. 2.47 +/- 0.12 micromol.(g protein)-1.min-1), maximal Ca2+ ATPase activity (Vmax, 152 +/- 12 vs. 119 +/- 9 micromol.(g protein)-1.min-1) and both phase 1 (15.1 +/- 0.98 vs. 13.1 +/- 0.28 micromol.(g protein)-1.min-1) and phase 2 (6.56 +/- 0.33 vs. 4.91 +/- 0.28 micromol.(g protein)-1.min-1) Ca2+ release in vastus lateralis muscle. No differences were observed between Norm CHO and Ex-Norm CHO in the response of these properties to exercise. Compared with Norm CHO, Ex+Norm CHO resulted in higher (p < 0.05) resting Ca2+ uptake (3.17 +/- 0.21 vs. 3.49 +/- 0.24 micromol.(g protein).min-1 and higher ionophore ratio, defined as the ratio of Vmax measured with and without the Ca2+-ionophore A23187, (2.3 +/- 0.3 vs. 4.4 +/- 0.3 micromol.(g protein).min-1) at fatigue. No differences were observed between conditions in the concentration of muscle glycogen, the high-energy phosphates (ATP and PCr), or metabolites (Pi, Cr, and lactate). Ex+Norm CHO also failed to modify the exercise-induced changes in CHO and fat oxidation. We conclude that prolonged exercise to fatigue performed 4 days following glycogen-depleting exercise while on a normal CHO diet elevates resting Ca2+ uptake and prevents increases in SR membrane permeability to Ca2+ as measured by the ionophore ratio.     

Thyroid status and endothelium-dependent vasodilation in skeletal muscle

Cardiovascular dysfunction is characteristic of both hypo- and hyperthyroidism. Endothelium-dependent dilation of conductance vessels is impaired in hypothyroidism but augmented in hyperthyroidism. We hypothesized that these alterations in dilation extend into the resistance vasculature of skeletal muscle. To test this hypothesis, rats were made hypothyroid with propylthiouracil (Hypo; n = 13) or hyperthyroid with triiodothyronine (Hyper; n = 9) over 3-4 mo. Compared with euthyroid controls (Eut; n = 14), Hypo rats were characterized by reduced skeletal muscle oxidative capacity and blunted growth; Hyper rats exhibited increased muscle oxidative capacity and left ventricular hypertrophy (P < 0.05 for all effects). Vasodilation to the endothelium-dependent agent acetylcholine ( approximately 2 x 10(-4) M) in skeletal muscle was determined in situ. Conductance in certain muscles increased from control [e.g., soleus: 0.98 +/- 0.15 (Eut), 0.79 +/- 0.14 (Hypo), and 1.06 +/- 0.24 ml.min(-1).100 g(-1).mmHg(-1) (Hyper); not significant among groups] to acetylcholine [1.91 +/- 0.21 (Eut), 2.28 +/- 0.26 (Hypo), and 2.15 +/- 0.33 ml.min(-1).100 g(-1).mmHg(-1) (Hyper); P < 0.05 vs. control values for all groups] but did not differ among groups. Expression of mRNA for the endothelial isoform of nitric oxide synthase in resistance vessels isolated from various muscles was similarly unchanged with alterations in thyroid status [e.g., soleus 1A arterioles: 33.15 +/- 0.58 (Eut), 32.73 +/- 0.27 (Hypo), and 32.80 +/- 0.54 (Hyper) cycles at threshold; not significant]. These data suggest that endothelium-dependent dilation of resistance vasculature in skeletal muscle is unchanged in both hypo- and hyperthyroidism. These data also emphasize the importance of examining resistance vasculature to improve understanding of effects of chronic disease on integrated cardiovascular function.     

Regulation of VO₂ kinetics by O₂ delivery: insights from acute hypoxia and heavy-intensity priming exercise in young men

This study examined the separate and combined effects of acute hypoxia (Hypo) and heavy-intensity "priming" exercise (Hvy) on pulmonary O(2) uptake (Vo(2p)) kinetics during moderate-intensity exercise (Mod). Breath-by-breath Vo(2p) and near-infrared spectroscopy-derived muscle deoxygenation {deoxyhemoglobin concentration [HHb]} were monitored continuously in 10 men (23 ± 4 yr) during repetitions of a Mod 1-Hvy-Mod 2 protocol, where each of the 6-min (Mod or Hvy) leg-cycling bouts was separated by 6 min at 20 W. Subjects were exposed to Hypo [fraction of inspired O(2) (Fi(O(2))) = 15%, Mod 2 + Hypo] or "sham" (Fi(O(2)) = 20.9%, Mod 2-N) 2 min following Hvy in half of these repetitions; Mod was also performed in Hypo without Hvy (Mod 1 + Hypo). On-transient Vo(2p) and [HHb] responses were modeled as a monoexponential. Data were scaled to a relative percentage of the response (0-100%), the signals were time-aligned, and the individual [HHb]-to-Vo(2) ratio was calculated. Compared with control (Mod 1), τVo(2p) and the O(2) deficit (26 ± 7 s and 638 ± 144 ml, respectively) were reduced (P < 0.05) in Mod 2-N (20 ± 5 s and 529 ± 196 ml) and increased (P < 0.05) in Mod 1 + Hypo (34 ± 14 s and 783 ± 184 ml); in Mod 2 + Hypo, τVo(2p) was increased (30 ± 8 s, P < 0.05), yet O(2) deficit was unaffected (643 ± 193 ml, P > 0.05). The modest "overshoot" in the [HHb]-to-Vo(2) ratio (reflecting an O(2) delivery-to-utilization mismatch) in Mod 1 (1.06 ± 0.04) was abolished in Mod 2-N (1.00 ± 0.05), persisted in Mod 2 + Hypo (1.09 ± 0.07), and tended to increase in Mod 1 + Hypo (1.10 ± 0.09, P = 0.13). The present data do not support an "O(2) delivery-independent" speeding of τVo(2p) following Hvy (or Hvy + Hypo); rather, this study suggests that local muscle O(2) delivery likely governs the rate of adjustment of Vo(2) at τVo(2p) greater than ～20 s.     

Severe hypoxia affects exercise performance independently of afferent feedback and peripheral fatigue

To test the hypothesis that hypoxia centrally affects performance independently of afferent feedback and peripheral fatigue, we conducted two experiments under complete vascular occlusion of the exercising muscle under different systemic O(2) environmental conditions. In experiment 1, 12 subjects performed repeated submaximal isometric contractions of the elbow flexor to exhaustion (RCTE) with inspired O(2) fraction fixed at 9% (severe hypoxia, SevHyp), 14% (moderate hypoxia, ModHyp), 21% (normoxia, Norm), or 30% (hyperoxia, Hyper). The number of contractions (performance), muscle (biceps brachii), and prefrontal near-infrared spectroscopy (NIRS) parameters and high-frequency paired-pulse (PS100) evoked responses to electrical muscle stimulation were monitored. In experiment 2, 10 subjects performed another RCTE in SevHyp and Norm conditions in which the number of contractions, biceps brachii electromyography responses to electrical nerve stimulation (M wave), and transcranial magnetic stimulation responses (motor-evoked potentials, MEP, and cortical silent period, CSP) were recorded. Performance during RCTE was significantly reduced by 10-15% in SevHyp (arterial O(2) saturation, SpO(2) = ～75%) compared with ModHyp (SpO(2) = ～90%) or Norm/Hyper (SpO(2) > 97%). Performance reduction in SevHyp occurred despite similar 1) metabolic (muscle NIRS parameters) and functional (changes in PS100 and M wave) muscle states and 2) MEP and CSP responses, suggesting comparable corticospinal excitability and spinal and cortical inhibition between SevHyp and Norm. It is concluded that, in SevHyp, performance and central drive can be altered independently of afferent feedback and peripheral fatigue. It is concluded that submaximal performance in SevHyp is partly reduced by a mechanism related directly to brain oxygenation.     

Prolonged exercise to fatigue in humans impairs skeletal muscle Na+-K+-ATPase activity, sarcoplasmic reticulum Ca2+ release, and Ca2+ uptake.

Prolonged exhaustive submaximal exercise in humans induces marked metabolic changes, but little is known about effects on muscle Na+-K+-ATPase activity and sarcoplasmic reticulum Ca2+ regulation. We therefore investigated whether these processes were impaired during cycling exercise at 74.3 +/- 1.2% maximal O2 uptake (mean +/- SE) continued until fatigue in eight healthy subjects (maximal O2 uptake of 3.93 +/- 0.69 l/min). A vastus lateralis muscle biopsy was taken at rest, at 10 and 45 min of exercise, and at fatigue. Muscle was analyzed for in vitro Na+-K+-ATPase activity [maximal K+-stimulated 3-O-methylfluorescein phosphatase (3-O-MFPase) activity], Na+-K+-ATPase content ([3H]ouabain binding sites), sarcoplasmic reticulum Ca2+ release rate induced by 4 chloro-m-cresol, and Ca2+ uptake rate. Cycling time to fatigue was 72.18 +/- 6.46 min. Muscle 3-O-MFPase activity (nmol.min(-1).g protein(-1)) fell from rest by 6.6 +/- 2.1% at 10 min (P <0.05), by 10.7 +/- 2.3% at 45 min (P <0.01), and by 12.6 +/- 1.6% at fatigue (P <0.01), whereas 3[H]ouabain binding site content was unchanged. Ca2+ release (mmol.min(-1).g protein(-1)) declined from rest by 10.0 +/- 3.8% at 45 min (P <0.05) and by 17.9 +/- 4.1% at fatigue (P < 0.01), whereas Ca2+ uptake rate fell from rest by 23.8 +/- 12.2% at fatigue (P=0.05). However, the decline in muscle 3-O-MFPase activity, Ca2+ uptake, and Ca2+ release were variable and not significantly correlated with time to fatigue. Thus prolonged exhaustive exercise impaired each of the maximal in vitro Na+-K+-ATPase activity, Ca2+ release, and Ca2+ uptake rates. This suggests that acutely downregulated muscle Na+, K+, and Ca2+ transport processes may be important factors in fatigue during prolonged exercise in humans.     

Effect of expiratory muscle fatigue on exercise tolerance and locomotor muscle fatigue in healthy humans

High-intensity exercise (> or =90% of maximal O(2) uptake) sustained to the limit of tolerance elicits expiratory muscle fatigue (EMF). We asked whether prior EMF affects subsequent exercise tolerance. Eight male subjects (means +/- SD; maximal O(2) uptake = 53.5 +/- 5.2 ml.kg(-1).min(-1)) cycled at 90% of peak power output to the limit of tolerance with (EMF-EX) and without (CON-EX) prior induction of EMF and for a time equal to that achieved in EMF-EX but without prior induction of EMF (ISO-EX). To induce EMF, subjects breathed against an expiratory flow resistor until task failure (15 breaths/min, 0.7 expiratory duty cycle, 40% of maximal expiratory gastric pressure). Fatigue of abdominal and quadriceps muscles was assessed by measuring the reduction relative to prior baseline values in magnetically evoked gastric twitch pressure (Pga(tw)) and quadriceps twitch force (Q(tw)), respectively. The reduction in Pga(tw) was not different after resistive breathing vs. after CON-EX (-27 +/- 5 vs. -26 +/- 6%; P = 0.127). Exercise time was reduced by 33 +/- 10% in EMF-EX vs. CON-EX (6.85 +/- 2.88 vs. 9.90 +/- 2.94 min; P < 0.001). Exercise-induced abdominal and quadriceps muscle fatigue was greater after EMF-EX than after ISO-EX (-28 +/- 9 vs. -12 +/- 5% for Pga(tw), P = 0.001; -28 +/- 7 vs. -14 +/- 6% for Q(tw), P = 0.015). Perceptual ratings of dyspnea and leg discomfort (Borg CR10) were higher at 1 and 3 min and at end exercise during EMF-EX vs. during ISO-EX (P < 0.05). Percent changes in limb fatigue and leg discomfort (EMF-EX vs. ISO-EX) correlated significantly with the change in exercise time. We propose that EMF impaired subsequent exercise tolerance primarily through an increased severity of limb locomotor muscle fatigue and a heightened perception of leg discomfort.     

Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m

Prevalence of excessive erythrocytosis, the main sign of chronic mountain sickness (CMS), is greater in postmenopausal Andean women than in premenopausal women. It is uncertain whether this greater prevalence is related to the decline in female hormones and ventilatory function after the occurrence of the menopause. To study this, we compared the physiological variables involved in the physiopathology of CMS [end-tidal CO(2) (PET(CO(2)), Torr) and end-tidal O(2) (PET(O(2)), Torr), arterial oxygen saturation (Sa(O(2)), %), and Hb concentration (g/dl)] and progesterone and estradiol levels between postmenopausal and premenopausal women, both in the luteal and follicular phases. Women residing in Cerro de Pasco (n = 33; 4,300 m) aged 26--62 yr were studied. Postmenopausal women compared with premenopausal women in the luteal phase had lower PET(O(2)) (48 +/- 4 vs. 53 +/- 2 Torr, P = 0.005) and Sa(O(2)) levels (82 +/- 12 vs. 88 +/- 12%, P < 0.005) and higher PET(CO(2)) (34 +/- 2 vs. 29 +/- 3 Torr, P = 0.005) and Hb concentration (19 +/- 1 vs. 14 +/- 2 g/dl, P < 0.005). In addition, plasma progesterone was negatively correlated with PET(CO(2)) and positively correlated with PET(O(2)) and Sa(O(2)). No clear relationship was found among the cycle phases between estradiol and the variables studied. In conclusion, our results reveal that, before menopause, there is better oxygenation and lower Hb levels in women long residing at altitude, and this is associated with higher levels of progesterone in the luteal phase of the cycle.     

Effects of progressive exercise and hypoxia on human muscle sarcoplasmic reticulum function.

This study examined the effects of progressive exercise to fatigue in normoxia (N) on muscle sarcoplasmic reticulum (SR) Ca(2+) cycling and whether alterations in SR Ca(2+) cycling are related to the blunted peak mechanical power output (PO(peak)) and peak oxygen consumption (Vo(2 peak)) observed during progressive exercise in hypoxia (H). Nine untrained men (20.7 +/- 0.42 yr) performed progressive cycle exercise to fatigue on two occasions, namely during N (inspired oxygen fraction = 0.21) and during H (inspired oxygen fraction = 0.14). Tissue extracted from the vastus lateralis before exercise and at power output corresponding to 50 and 70% of Vo(2 peak) (as determined during N) and at fatigue was used to investigate changes in homogenate SR Ca(2+)-cycling properties. Exercise in H compared with N resulted in a 19 and 21% lower (P < 0.05) PO(peak) and Vo(2 peak), respectively. During progressive exercise in N, Ca(2+)-ATPase kinetics, as determined by maximal activity, the Hill coefficient, and the Ca(2+) concentration at one-half maximal activity were not altered. However, reductions with exercise in N were noted in Ca(2+) uptake (before exercise = 357 +/- 29 micromol x min(-1) x g protein(-1); at fatigue = 306 +/- 26 micromol x min(-1) x g protein(-1); P < 0.05) when measured at free Ca(2+) concentration of 2 microM and in phase 2 Ca(2+) release (before exercise = 716 +/- 33 micromol x min(-1) x g protein(-1); at fatigue = 500 +/- 53 micromol x min(-1) x g protein(-1); P < 0.05) when measured in vitro in whole muscle homogenates. No differences were noted between N and H conditions at comparable power output or at fatigue. It is concluded that, although structural changes in SR Ca(2+)-cycling proteins may explain fatigue during progressive exercise in N, they cannot explain the lower PO(peak) and Vo(2 peak) observed during H.     

Effects of assuming constant optical scattering on measurements of muscle oxygenation by near-infrared spectroscopy during exercise.

The aim of this study was to examine the effects of assuming constant reduced scattering coefficient (mu'(s)) on the muscle oxygenation response to incremental exercise and its recovery kinetics. Fifteen subjects (age: 24 +/- 5 yr) underwent incremental cycling exercise. Frequency domain near-infrared spectroscopy (NIRS) was used to estimate deoxyhemoglobin concentration {[deoxy(Hb+Mb)]} (where Mb is myoglobin), oxyhemoglobin concentration {[oxy(Hb+Mb)]}, total Hb concentration (Total[Hb+Mb]), and tissue O(2) saturation (Sti(O(2))), incorporating both continuous measurements of mu'(s) and assuming constant mu'(s). When measuring mu'(s), we observed significant changes in NIRS variables at peak work rate Delta[deoxy(Hb+Mb)] (15.0 +/- 7.8 microM), Delta[oxy(Hb+Mb)] (-4.8 +/- 5.8 microM), DeltaTotal[Hb+Mb] (10.9 +/- 8.4 microM), and DeltaSti(O(2))(-11.8 +/- 4.1%). Assuming constant mu'(s) resulted in greater (P < 0.01 vs. measured mu'(s)) changes in the NIRS variables at peak work rate, where Delta[deoxy(Hb+Mb)] = 24.5 +/- 15.6 microM, Delta[oxy(Hb+Mb)] = -9.7 +/- 8.2 microM, DeltaTotal[Hb+Mb] = 14.8 +/- 8.7 microM, and DeltaSti(O(2))= -18.7 +/- 8.4%. Regarding the recovery kinetics, the large 95% confidence intervals (CI) for the difference between those determine measuring mu'(s) and assuming constant mu'(s) suggested poor agreement between methods. For the mean response time (MRT), which describes the overall kinetics, the 95% confidence intervals were MRT - [deoxy(Hb+Mb)] = 26.7 s; MRT - [oxy(Hb+Mb)] = 11.8 s, and MRT - Sti(O(2))= 11.8 s. In conclusion, mu'(s) changed from light to peak exercise. Furthermore, assuming a constant mu'(s) led to an overestimation of the changes in NIRS variables during exercise and distortion of the recovery kinetics.     

Inflection points of cardiovascular responses and oxygenation are correlated in the distal but not the proximal portions of muscle during incremental exercise.

To test whether there is a regional difference in the exercise pressor reflex within a given muscle, we investigated the relationship between the inflection points of cardiovascular responses and muscle oxygenation during exercise. Seven subjects performed incremental exercise, which consisted of incremental 30-s static knee extensions, each separated by 30 s of recovery. The workload started at 5% maximal voluntary contraction (MVC) and increased by 5% MVC for each increment until exhaustion. Changes (Delta) in the concentrations (denoted by brackets) of oxygenated Hb (O2Hb) and deoxygenated Hb (HHb) were monitored in proximal and distal portions of the vastus lateralis by near-infrared spectroscopy. The inflection points of mean arterial pressure (MAP), calf vascular resistance (CVR), and muscle deoxygenation index (Delta[O2Hb-HHb]) were calculated as the intersection point of two regression equations obtained at lower and higher workloads. The inflection point of Delta[O2Hb-HHb] differed significantly between proximal and distal portions (28.5 +/- 3.0 vs. 39.5 +/- 3.0%MVC, P < 0.05). Linear regression analysis showed significant correlations between the inflection point of Delta[O2Hb-HHb] in the distal portion and MAP (r = 0.89; P < 0.01) and CVR (r = 0.89; P < 0.05), but no significant relationship between the inflection point in the proximal portion and MAP or CVR. These data show that the inflection point of muscle deoxygenation differs between proximal and distal portions within the vastus lateralis during incremental exercise and suggest that the distal portion of the vastus lateralis contributes more to the pressor response than does the proximal portion.