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Background: Tissue iron depletion may negatively affect endurance performance and muscle fatigability. Objective: We investigated tissue-level iron depletion and progressive fatigue of the quadriceps during dynamic knee-extension exercise in young women. Design: Twenty iron-depleted (serum ferritin < 20 [micro]g/L), nonanemic (hemoglobin > 110 g/L) women ([bar]x [+ or -] SEM age: 29.1 [+ or -] 1.2 y) received iron (iron group) or placebo (placebo group) for 6 wk in a randomized, double-blind trial (n = 10 per group). A protocol integrating 2-3-s maximal voluntary static contractions (MVCs) with dynamic knee extensions was used to assess fatigue. Results: No significant differences between the groups in baseline iron status, MVC at rest, or MVC at the end of the protocol were observed. After treatment, serum iron and transferrin saturation increased significantly in the iron group (P = 0.02 and P = 0.03, respectively). Serum transferrin receptor concentrations increased significantly in the placebo group (P < 0.01) but not in the iron group. After treatment, the rate of decrease in MVC was attenuated in the iron group but not in the placebo group (P = 0.01). In the iron group, MVC at the sixth minute of the fatigue protocol and MVC at the end of the protocol were [approximately equal to] 15% (P = 0.04) and [approximately equal to] 27% higher (P < 0.01), respectively, after treatment. These improvements were not related to changes in iron-status indexes or tissue iron stores, although power was low (< 0.50) to detect these relations. Conclusions: Iron supplementation was associated with a significant improvement in muscle fatigability. Interpretation regarding the direct role of tissue iron status is limited by the study's low power to detect relations between tissue iron improvement and decreased muscle fatigue KEY WORDS Quadriceps femoris, leg kick, iron deficiency, endurance, oxidative capacity, mitochondrial respiration, Mexican women

ABSTRACTRecent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1methylation. The number of years lived at high altitude was negatively associated with EPAS1methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1rs2236225, TYMSrs502396, FOLH1rs202676, GLDCrs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.

This study tested the hypothesis that Andean natives are adapted to high altitude (HA) via high work efficiency during exercise in hypoxia. A total of 186 young males and females were tested in Bolivia, comprising eight different subject groups. Groups were identified based on gender, ancestry (Aymara vs. European), altitude of birth (highlands vs. lowlands), and the altitude where tested (420, 3600, 3850 m). This design allows partitioning of ancestral (i.e., genetic) and developmental effects. To minimize measurement error, subjects were given two submaximal exercise tests on a cycle ergometer (on separate days). Each test consisted of four 5-min work bouts (levels), each separated by a 5-min rest period. For all groups, the oxygen consumption (VO2)-work rate relationship was not different from the sea-level reference. Gross and net efficiencies (GE and NE) were not different between groups at any work level, with the exception of European men born in the lowlands and acclimatized and tested at 3600 m. These men showed slightly lower VO2 at high work output, but this may be due to a nonsteady-state VO2 kinetic, rather than to an altered steady-state VO2-work rate relationship per se. There were no significant group differences in delta efficiency (DE). In sum, these results provide no support for the hypothesis of energetic advantage during submaximal work in Andean HA natives. A review and analysis of the literature suggest that the same is true for HA natives in the Himalayas.

Many physiological and anthropological studies have investigated the unique Andean and Himalayan populations that have resided for many hundreds of generations at high altitude (HA). A nonscientific survey of the extant literature reveals a relatively liberal tradition of inferring genetic (evolutionary) adaptation to HA in these groups, often based on limited evidence and/or based on study designs insufficient to fully address the issue. In order to provide some perspective, I review relevant methodological issues that should be considered before evolutionary inference is made. On the whole, this paper takes a conservative stance and cautions against evolutionary inference based on the serious limitations of currently applied research approaches.

Exercise-induced arterial hypoxemia (EIAH) has been reported in male athletes, particularly during fast-increment treadmill exercise protocols. Recent reports suggest a higher incidence in women. We hypothesized that 1-min incremental (fast) running (R) protocols would result in a lower arterial Po2(PaO2) than 5-min increment protocols (slow) or cycling exercise (C) and that women would experience greater EIAH than previously reported for men. Arterial blood gases, cardiac output, and metabolic data were obtained in 17 active women [mean maximal O2uptake (V˙o2 max) = 51 ml · kg−1· min−1]. They were studied in random order (C or R), with a fastV˙o2 maxprotocol. After recovery, the women performed 5 min of exercise at 30, 60, and 90% ofV˙o2 max(slow). One week later, the other exercise mode (R or C) was similarly studied. There were no significant differences in V˙o2 maxbetween R and C. Pulmonary gas exchange was similar at rest, 30%, and 60% of V˙o2 max. At 90% ofV˙o2 max, PaO2was lower during R (mean ± SE = 94 ± 2 Torr) than during C (105 ± 2 Torr, P< 0.0001), as was ventilation (85.2 ± 3.8 vs. 98.2 ± 4.4 l/min btps,P< 0.0001) and cardiac output (19.1 ± 0.6 vs. 21.1 ± 1.0 l/min, P< 0.001). Arterial Pco2(32.0 ± 0.5 vs. 30.0 ± 0.6 Torr,P< 0.001) and alveolar-arterial O2difference (A-aDo2; 22 ± 2 vs. 16 ± 2 Torr,P< 0.0001) were greater during R. PaO2and A-aDo2were similar between slow and fast. Nadir PaO2was ≤80 Torr in four women (24%) but only during fast-R. In all subjects, PaO2atV˙o2 maxwas greater than the lower 95% prediction limit calculated from available data in men (n= 72 C and 38 R) for both R and C. These data suggest intrinsic differences in gas exchange between R and C, due to differences in ventilation and also efficiency of gas exchange. The PaO2responses to R and C exercise in our 17 subjects do not differ significantly from those previously observed in men.

Noninvasive measurement of cardiac output (Q˙t) is problematic during heavy exercise. We report a new approach that avoids unpleasant rebreathing and resultant changes in alveolarPO2orPCO2by measuring short-term acetylene (C2H2) uptake by an open-circuit technique, with application of mass balance for the calculation ofQ˙t. The method assumes that alveolar and arterial C2H2pressures are the same, and we account for C2H2recirculation by extrapolating end-tidal C2H2back to breath 1of the maneuver. We correct for incomplete gas mixing by using He in the inspired mixture. The maneuver involves switching the subject to air containing trace amounts of C2H2and He; ventilation and pressures of He, C2H2, and CO2are measured continuously (the latter by mass spectrometer) for 20–25 breaths. Data from three subjects for whom multiple Fick O2measurements ofQ˙twere available showed that measurement ofQ˙tby the Fick method and by the C2H2technique was statistically similar from rest to 90% of maximal O2consumption (V˙o2 max). Data from 12 active women and 12 elite male athletes at rest and 90% ofV˙o2 maxfell on a single linear relationship, with O2consumption (V˙o2) predictingQ˙tvalues of 9.13, 15.9, 22.6, and 29.4 l/min atV˙o2of 1, 2, 3, and 4 l/min. Mixed venous PO2predicted from C2H2-determinedQ˙t, measuredV˙o2, and arterial O2concentration was ∼20–25 Torr at 90% ofV˙o2 maxduring air breathing and 10–15 Torr during 13% O2breathing. This modification of previous gas uptake methods, to avoid rebreathing, produces reasonable data from rest to heavy exercise in normal subjects.

Chest depth, chest width, forced vital capacity (FVC), and forced expiratory volume (FEV1) were measured in 170 adult males differing by ancestral (genetic) and developmental exposure to high altitude (HA). A complete migrant study design was used to study HA natives (Aymara/Quechua ancestry, n = 88) and low altitude (LA) natives (European/North American ancestry, n = 82) at both altitude (La Paz, Bolivia, 3,600 m) and near sea level (Santa Cruz, Bolivia, 420 m). HAN and LAN migrant groups were classified as: N^th generation migrants, born and raised in a non-native environment; child migrants who migrated during the period of growth and maturation (0–18 yrs); and adult migrants who migrated after 18 years of age. Chest depth, FVC, and FEV1 measures were larger with increasing developmental exposure in both HAN migrants at LA and LAN migrants at HA. Developmental responses were similar between HAN and LAN groups. FVC and FEV1 measures were larger in HANs vs LANs born and raised at HA to suggest a genetic effect, but were similar in HANs and LANs born and raised at LA. The similarity of HAN and LAN groups at LA suggests that the genetic potential for larger lung volumes at HA depends upon developmental exposure to HA. Additional data for females (HANs at HA, n = 20, and LAN adult migrants to HA, n = 17) show similar differences as those shown between male HAN and LAN groups. Am. J. Hum. Biol. 11:383–395, 1999. © 1999 Wiley-Liss, Inc.