Exercise Capacity and Selected Physiological Factors by Ancestry and Residential Altitude: Cross-Sectional Studies of 9–10-Year-Old Children in Tibet

Introduction

Approximately 17 million of the world's population lives at altitudes higher than 3500 m above sea level (Huddleston et al., 2003). In the Tibet Autonomous Region (TAR) of China, more than 2.8 million people (2009) live at similar altitudes, of whom 92% are native Tibetans and 8% are Han immigrants from lowland China (Han Chinese). Native Tibetans have the longest history of living at high altitude among world populations, approximately 22,000 years (approximately 1100 generations) (Niermeyer et al., 2001; Aldenderfer, 2003), as compared with Han Chinese immigrants, who have lived at high altitude in Tibet for 1–3 generations only.

Most previous studies have shown that native Tibetan adults (Sun et al., 1990; Groves et al., 1993; Zhuang et al., 1993; 1996) and adolescents (Chen et al., 1997) achieve a superior exercise capacity compared to Han Chinese immigrants. However, a few studies have shown that native Tibetan adults attained a higher exercise capacity, but a similar (Niu et al., 1995) or lower (Ge et al.,1994) peak oxygen uptake ( \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes {10} {9} {7} {6} \begin{document} $$\dot{\rm V}\rm O_{2 {\rm peak}}$$ \end{document} ). \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes {10} {9} {7} {6} \begin{document} $$\dot{\rm V}\rm O_{2 {\rm peak}}$$ \end{document} is considered the best single measure of cardiorespiratory fitness (Astrand and Rodahl, 1986), which provides a good index of the integrated function of the oxygen transport system in both children and adults. \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes {10} {9} {7} {6} \begin{document} $$\dot{\rm V}\rm O_{2 {\rm peak}}$$ \end{document} can be estimated from maximal power output (W_max) (Woynarowska,1980; Hansen et al., 1989; Andersen et al., 1987; Andersen, 1995; Arngrimsson et al., 2008; Bianba et al., 2010), and has been used in the evaluation of the adaptation to live and work at high altitude (Grover et al.,1967; Ge et al.,1994; Wu and Kayser, 2006).

A person who moves from sea level to Lhasa (3700 m) will acclimatize after some days, but even after decades he or she will not reach a sea level performance of exercise or work. A person arriving in Lhasa from sea level can expect to reach an exercise performance or work that is approximately 70% of his or her performance at sea level, which will increase to 80% after a few weeks of acclimatization (Moore et al., 1994). Similar to the immigrant Han Chinese in Tibet, if a person stays at 3700 m for years, there may be a further small increase to nearly 85% of the initial sea level value (Moore et al., 1994). After generations of residence, Tibetans at 3700 m have an exercise performance or work that is 92% of sea level values for sedentary populations (Moore et al., 1994).

In relation to both a decrease in arterial oxygen content and a limitation in maximal cardiac output, moving lowlanders to higher altitudes is associated with a decreased aerobic exercise capacity (Fulco et al., 1998), while a higher pre-exposure residential altitude modulates the negative effect (Fulco et al., 1998). High altitude populations are continuously challenged in an environment of hypobaric hypoxia with a low ambient partial pressure of oxygen, thus influencing the capacity for work and exercise. Moreover, the capacity is reduced with an increasing residential altitude (Fulco et al., 1998). However, if high altitude natives move to a lower altitude, they will exhibit a better exercise capacity than natives living at the same, lower altitude, as demonstrated by Curran et al. (1998). The relatively better maximal exercise capacity in high altitude natives may primarily be due to their exposure to a high altitude environment during childhood (Frisancho et al., 1973). Independent of being a child or an adult, or of a low or high socioeconomic status, everyone is exposed to the same ambient hypoxia at a given altitude. As reviewed by Simonsen et al. (2012), native highland populations have genetic adaptations that enable them to live at high altitudes. Three out of several genes associated with natural selection among Tibetans, EPAS1, EGLN1, and PPARA, are associated with their relatively low hemoglobin concentration (Simonson et al., 2012).

In a review by Wu and Kayser (2006), they concluded that among adults, Tibetans were better adapted than other populations to live and work at high altitudes. In addition to a lower Hb concentration, as compared with lowlanders and Andeans living at the same altitude, several other physiological factors contributed to this adaptation, including: maintaining a higher arterial oxygen saturation at rest and during exercise, less loss of aerobic performance with an increasing altitude, a greater hypoxic and hypercapnic ventilatory responsiveness, larger lungs, a better lung function, and a greater lung diffusing capacity than lowlanders (Wu and Kayser, 2006). Lastly, Tibetans develop only minimal hypoxic pulmonary hypertension (Groves et al., 1993), and have higher levels of exhaled nitric oxide than lowlanders or Andeans (Wu and Kayser, 2006). Studies of physiological aspects of Tibetan children's capacity to work and live at high altitude are scarce, although differences similar to those seen in adults may be expected to occur. Children living at altitudes higher than 3000 m above sea level show several adaptive mechanisms in the uptake of oxygen in terms of increased ventilation and pulmonary diffusion capacity (de Meer et al., 1995). The latter depends on the diffusion rate per unit of the surface area and the total surface area in the lungs available for diffusion of oxygen, which is reflected in part by total lung capacity (de Meer et al., 1995). Oxygen transportation in the blood is highly dependent on blood flow, hemoglobin concentration ([Hb]), and arterial oxygen saturation (S_ao₂) (Astrand, 1986).

The objectives of the present study were to compare exercise capacity (maximal power output) and selected physiological factors (arterial oxygen saturation and heart rate at rest and during maximal exercise, resting hemoglobin concentration, and forced vital capacity) in groups of high altitude native Tibetan children across residential altitudes (3700 vs. 4300 m above sea level) and across ancestry (native Tibetan vs. Han Chinese children living at the same altitude of 3700 m). We also aimed to investigate the association of residential altitude and ancestry with exercise capacity, and the possible impact of selected physiological factors on this association.

Materials and Methods

Nine primary schools out of 20 were randomly selected from Lhasa City (3700 m), the capital of TAR, while all five primary schools were included from the rural Tingri district (4300 m) located under the North Face of Mt. Everest. An identical procedure for selecting participants was applied in both areas, and all 9–10-year-old children, 817 children from Lhasa and 460 children from Tingri, were invited. In Lhasa, one child refused to participate and four children on the list were excluded due to respiratory health problems, yielding 812 eligible children, which gave a participation rate of 99%. A total of 406 native Lhasa Tibetan children (207 boys and 199 girls) and 406 Lhasa Han Chinese children (235 boys and 171 girls) participated in the urban area. Among the Han Chinese, 313 (77%) were born at low altitude (lowland-born Han Chinese) and then migrated to Lhasa with their parents, while the remaining 93 (23%) were born in Lhasa (highland-born Han Chinese). In Tingri, 16 did not go to school on the days of the data collection and four children refused to participate, whereas 10 children participated but did not give permission to use their data for publication, thus yielding a response rate of 93%. A total of 215 girls and 215 boys participated from Tingri.

Results

The sex-specific descriptive data of Tingri Tibetan, Lhasa Tibetan, and Lhasa Han Chinese children are presented in Table 1. On average, the Lhasa Tibetans were 32% and 7% heavier than Tingri Tibetans and Lhasa Han Chinese, respectively. Furthermore, they were 10% and 1% taller, and had 8% and 4% larger chest circumferences than Tingri Tibetans and Lhasa Han Chinese, respectively.

Physiological factors

The [Hb] was 5% higher in Lhasa Han Chinese compared with Lhasa Tibetans, and 4% higher in Lhasa Tibetans than in Tingri Tibetans. The lung volume (FVC) and peak heart rate (HR_peak) were higher in Lhasa Tibetans than both Lhasa Han Chinese and Tingri Tibetans. Lhasa Tibetan achieved 46% and 10% higher levels of absolute W_max (W) than Tingri Tibetan and Lhasa Han Chinese, respectively, and 20% (21.8% in boys and 18.5% in girls) and 4% (5.8% in boys and 2.1% in girls) higher levels of relative W_max (W/kg), respectively (Table 1).

There was no difference in arterial oxygen saturation at rest (S_aO_2rest) between Lhasa Tibetans and Lhasa Han Chinese (i.e., no difference by ancestry), although a difference was found by residential altitude (Tingri vs. Lhasa) (Fig. 1). At rest, Lhasa Tibetan boys had a higher S_aO_2rest (91%±2.7%) than Tingri Tibetan boys (87%±3.5%, p<0.001), while Lhasa Tibetan girls had a higher S_aO_2rest (91%±2.6%) than both Tingri Tibetan girls (88%±3.2%, p<0.001) and Lhasa Han Chinese girls (90%±3.3%, p=0.013) (not shown in table). The oxygen saturation gradually decreased with an increasing power output for all three groups of children (Fig. 1), and at maximal power output, Lhasa Tibetan children had a significantly higher arterial oxygen saturation (S_aO_2peak) than both Tingri Tibetans (boys: 88%±3.7% vs. 82%±6.3%, p<0.001; girls: 88%±3.6% vs. 82%±6.7%, p<0.001), and Lhasa Han Chinese (boys: 88%±3.7% vs. 85%±4.8 %, p<0.001; girls: 88%±3.6% vs. 85%±4.8%, p<0.001).

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FIG. 1.

Alterations in arterial oxygen saturation (S_aO₂) from rest to maximal exercise based on the cycle ergometer test in 9–10-year-old Tingri Tibetan, Lhasa Tibetan, and Lhasa Han Chinese children. Values are presented as means (95% CI) (y-axis: % S_aO₂; x-axis: % of maximal power output (W_max)).

Discussion

In the present study we have shown that native Lhasa Tibetan 9–10-year-old children presented a higher exercise capacity than both native Tingri Tibetans and Lhasa Han Chinese when measured at their respective residential altitudes. [Hb], S_aO_2rest, S_aO_2peak, HR_peak, and FVC were all associated with exercise capacity, but did not significantly impact on the associations between residential altitude and ancestry with exercise capacity (maximal power output, W_max). Moreover, native Tibetans exhibited a lower [Hb] and higher S_aO_2rest than Han Chinese living at the same altitude, whereas native Tibetans at 4300 m had a lower [Hb] than native Tibetans at 3700 m.

Compared to Lhasa Tibetan children living at 3700 m, the lower maximal power output in native Tingri Tibetans living at 4300 m may be due to the reduction in the inspired partial pressure of oxygen (P_iO₂). Furthermore, children's growth and development are closely correlated with their work and exercise performance, as well as altitude adaptation (Frisancho et al., 1975; 1985). The present study reveals that Tingri Tibetan children were shorter and lighter than Tibetan children from Lhasa of the same age, and such findings are consistent with a previous comparative study of Tibetan children and adolescents aged 7–18 years living at various altitudes from 2261 m to 4040 m in Qinghai-Tibet. The children from the highest altitude (4040 m) presented a slower growth (stature), lagging behind their counterparts at 2261 m by approximately 2 years. It was also indicated that hypoxia may be the main agent responsible for this delayed growth (Zhang et al., 1985), and Greksa et al. (1984) suggested that socioeconomic factors slowed the growth of high-altitude children (Greksa et al., 1984). In the present study, we have no valid information on socio-economic status (SES). It is a challenge to identify an indicator of SES that is valid for both Lhasa and Tingri. For example, in Tingri, parents generally have a low or no education and no income, but they may have many Yak or sheep, thus indicating a high SES. In contrast, in Lhasa, parents seldom own animals, and most males have an education, as well as income.

We speculate that the present finding of a lower [Hb] among Tingri Tibetan children compared with Lhasa Tibetan children, which stands in contrast to previous reports of an increase in [Hb] with an increasing altitude (Wu et al., 2005), may be due to poor nutrition, including less iron-rich foods at high altitude.

The present finding of a higher maximal power output in native Tibetan- compared to Han Chinese children at the same altitude may be due to a better oxygen transport system. The difference in oxygen concentration between arterial- and mixed-venous blood is a measure of tissue oxygen extraction, which can be inferred from [Hb] and the difference between the oxygen saturation in arterial- and mixed-venous blood (S_ao₂ - S_vo₂) (de Meer et al., 1995). In comparison with Han Chinese, a lower [Hb] in adult native Tibetans has previously been reported (Curran et al., 1997; Beall et al., 1998; Moore, 2000; Garruto et al., 2003; Wu et al., 2005). Additionally, the lower [Hb] in Tibetan subjects has been suggested to be a result of adaptation over many generations (Wu et al., 2005; Simonson et al., 2012), which has further been suggested to be more favorable than Andeans, who are characterized by a raised [Hb] (Stuber and Scherrer, 2010). Recent genetic studies identified genetic variants in native Tibetans living between 3200 and 4300 m compared with Han Chinese lowlanders (Beall et al., 2010; Bigham et al., 2010; Simonson et al., 2010; Yi et al., 2010; Peng et al., 2011; Xiang et al., 2013). Three genes, EPAS1, EGLN1, and PPARA, have been shown to be associated with hemoglobin concentration (Simonson et al., 2012), while no associations were found with EPAS1 and EGLN1 in Andeans (Bigham et al., 2013). Hence, genetic factors may explain the lower [Hb] in Lhasa Tibetans compared with Han Chinese in the present study.

Although the present Lhasa Tibetan children also had a lower [Hb] than Han Chinese, they sustained a higher S_aO₂ during maximal exercise than Lhasa Han Chinese children. This phenomenon could be explained by better maintained ventilation and/or a regulated production of [Hb] (Niermeyer et al., 2001). According to Moore et al. (1992), it is not likely that a leftward shift in the oxyhemoglobin dissociation curve in Lhasa Tibetans could help explain the present finding. As with other high altitude populations, they reported that the position of the Hb-O₂ dissociation curve in Tibetans was the same as that seen in sea level populations (Moore et al., 1992). We suppose that the higher S_aO₂ across the entire range of exercise intensities in Lhasa Tibetan children may indirectly reflect their smaller alveolar-arterial O₂ gradients ((A-a) DiffO₂), thereby indicating a larger diffusion capacity. If this assumption is correct for children, they may better maintain oxygen saturation during exercise compared to Han Chinese children (Zhuang et al., 1996; Wu and Kayser, 2006). It has been suggested that diffusion capacity could be a decisive factor for oxygen transport during maximal exercise at high altitude (Chen et al., 1997), and De Meer et al. summarized that an increase in pulmonary diffusion capacity facilitates oxygen delivery to the tissues in both children and adults living at higher altitudes (de Meer et al., 1995). As shown in several studies, an increased lung volume is also accompanied by an increased pulmonary diffusion capacity (DeGraff et al., 1970; Guleria et al., 1971; Cerny et al., 1973; Johnson et al., 1985; Sun et al., 1990; Armstrong and Welsman, 1994). Moreover, large lung volumes and chest circumferences have been reported among schoolchildren and adolescents who are native to high altitude (Frisancho, 1969; Beall et al., 1977), though not in immigrants acclimatized to high altitude (Frisancho et al., 1973). In the present study, native Lhasa Tibetan children had a significantly larger FVC and chest circumference than Lhasa Han Chinese children, even after adjusting for body mass and stature (data not shown).

A large sample size and high participation rates are strengths of the present study, while a weakness is that the study could have underestimated the exercise capacity for children who were less accustomed to cycling. However, the adjustment by the variable “owning a bicycle” in Models 1–3 may have partly compensated for differential cycling practices across the three groups of children. A selection of healthier children for the schools in rural Tingri may have taken place because of the need to be sufficiently physically healthy to walk the long way to school, and to live at the school dormitory for long periods. This is in contrast to urban Lhasa children, who are staying with their families, and have short travel distances. As a result, this possible selection would most likely have distorted the results towards a smaller difference between Tingri- and Lhasa children.

Conclusion

The superior exercise capacity in native Tibetan children vs. Han Chinese immigrant children living at the same altitude of 3700 m may reflect a better adaptation to life at high altitude. The lower exercise capacity at a higher altitude in native Tibetans may partially be attributed to residential altitude differences. In addition to residential altitude and ancestry, selected physiological parameters explained some of the variance in exercise capacity, including higher arterial oxygen saturation and a higher forced vital capacity, but these physiological factors did not fully account for the associations between residential altitude and ancestry with a maximal power output. Future studies comparing Tibetan and Han Chinese children living at the same altitude should also take genetic factors into account, in addition to potentially unmeasured confounders such as SES and food habits. These confounders should also be included in future studies comparing native Tibetans living at different altitudes.