Champions of the mountains: superior aerobic performance in Tibetans is not due to enhanced cardiopulmonary traits

Adequate oxygen uptake and delivery to working muscles is a fundamental determinant of aerobic exercise performance. In the austere environment of high altitude, reduced oxygen availability substantively curtails maximum aerobic performance. Adaptation to high altitude has allowed some populations, most notably the Sherpa people of the Himalayas, to thrive in conditions of hypobaric hypoxia. Interestingly, cardiopulmonary haemodynamics are similar between lowlander people of Caucasian/European ancestry and Sherpas (Faoro et al., 2014). However, a prior report described lower mean pulmonary artery pressures at rest and during exercise for a given level of hypoxia in a small sample of Tibetans compared with lowlanders (Groves et al., 1993). In this issue of The Journal of Physiology, Möller et al. (2024) sought to extend and validate previous findings by comparing Tibetan with Han Chinese participants to test the hypothesis that superior aerobic exercise capacity in Tibetans relates to physiologically advantageous cardiopulmonary haemodynamics, exemplified by lower pulmonary artery pressure at rest and increased blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) during exercise, in conditions of normoxia and hypobaric hypoxia. To investigate this hypothesis, young recreationally active males were recruited. Tibetan participants were born and raised at altitudes of >3500 m, while the Han Chinese participants resided in the city of Xining, at 2275 m. Comprehensive echocardiographic screening allowed a comparison of cardiac structure and function assessed at rest and during exercise on a cycle ergometer in a pressure chamber simulating sea level and 5000 m altitude. No differences were observed in cardiac output between groups, illustrating a lack of functional enhancement in the hearts of Tibetans. Augmented cardiac output would have provided a mechanistic basis for improved performance in Tibetan participants, due to a greater delivery of oxygen to working muscles consistent with the recognised positive correlation between increased cardiac output and improved maximal aerobic power and capacity. Pulmonary artery systolic pressure was not reduced during exercise in Tibetans and blood flow through IPAVAs was similar in the Tibetan and Han Chinese participants across most exercise intensities, at sea level and high altitude. Notwithstanding the unexpected similarities in cardiopulmonary haemodynamics, enhanced exercise capacity (greater V̇O2peak at 5000 m) was observed in Tibetans compared with Han Chinese, consistent with previous work on people native to high altitude. Furthermore, the Tibetans achieved greater peak power output during exercise, both at sea level and at altitude. Therefore, it is evident that improved aerobic exercise performance in Tibetans, like Sherpas, is unrelated to improved cardiopulmonary traits. Structural adaptations in the microvasculature of skeletal muscle could ostensibly be key, as increased muscle capillary density is a plausible mechanism that could contribute to superior performance in Tibetans at altitude. Angiogenesis occurs in response to low levels of cellular oxygen through activation of the master regulator of the hypoxic response, the hypoxia-inducible factor pathway, leading to the expression of vascular growth factors, stimulating the sprouting of new capillary branches. At the interface of muscle, greater capillary density increases the diffusion area, shortens the diffusion distance between vasculature and mitochondria, and slows the transit time of red blood cells, facilitating improved oxygen extraction. Interestingly, however, the number of capillaries per muscle fibre in the vastus lateralis is equivalent in lowland Tibetans compared with Nepalese lowlanders, but the cross-sectional area of fibres is smaller in Tibetans, which decreases the diffusion distance. Mean fibre area is also lower in Bolivian Aymara, lifelong residents at high altitude, compared with sea-level residents. Surprisingly, the capillary to fibre ratio is lower in Bolivian highlanders than sea-level residents who show no change in fibre area or capillary density after 8 weeks of residency at 4100 m. It is recognised, however, that adaptation to hypoxia differs between Tibetan and Andean populations with elevated red blood cell mass in the latter. Improved diffusion of oxygen to muscle mitochondria as a potential contributor to increased performance in Tibetans is acknowledged by the authors, noting prior reports in Sherpas. Of note, endurance exercise at ∼ 60–80% V̇O2max has been shown to be adequate to produce a 10–40% increase in muscle capillary density in untrained individuals within 4–8 weeks (Hellsten & Nyberg, 2015), demonstrating an impressive inherent capacity for vascular remodelling even in response to moderate intensity exercise. Oxygen extraction is enhanced in exercising lowlanders during acute exposure to hypoxia (Bourdillon et al., 2023), again revealing scope for functional plasticity over short time domains. But these changes pale in significance compared with the extraordinary feats of high-altitude adapted populations. As expected, haematocrit did not differ between Tibetans and Han Chinese participants, revealing that improved performance in the former does not relate to improved oxygen-carrying capacity. Unravelling the intricacies of the signalling processes responsible for the enhanced performance in Tibetans will require a shift in focus from integrative physiology to the molecular domain, exploiting the power of 'omics' approaches (Bourdillon et al., 2023). Oxygen utilisation remains a centrepiece in the consideration of the work of Möller & colleagues (2024). Previous work by the same group reported differences in blood flow distribution between Tibetan and Han Chinese during exercise at high altitude, with evidence that Tibetans prioritise oxygenation of the brain at the expense of muscle during hypoxic exercise (Fan et al., 2021). Despite demonstrably lower oxygenation of the vastus lateralis, Tibetans exhibit greater exercise efficiency in outperforming Han Chinese participants by ∼32% during hypoxia. This draws focus to an important distinction between maximal aerobic power and maximal aerobic capacity. Whereas aerobic power (V̇O2max) encompasses oxygen delivery and extraction, aerobic capacity defines the maximal amount of ATP that can be generated via oxidative metabolic processes. The latter is often quantified indirectly as the maximum work that can be performed aerobically in a given time, or at a given percentage of V̇O2max. In this manner, an individual's aerobic capacity represents their combined physiological capability for oxygen delivery and extraction, but also utilisation of oxygen within muscle. Improved muscle oxygen economy in Tibetans benefits their performance capability in hypoxic conditions. Indeed, whereas improvements in V̇O2max are typically limited to about 10–20% beyond the genetically determined base, overall improvements in aerobic capacity are often much greater and correlate well with enhancements in factors such as mitochondrial density and oxidative enzyme activity. These factors are responsive to even short exposures to hypoxia within a life cycle. Adaptation across generations to include epigenetic influences on cellular metabolic pathways, with improved efficiency in oxygen utilisation, energy sparing through suppression of ATP-dependent pathways, and mitigation of oxidative stress, amongst other factors, likely contribute to the relatively spared maximal performance of high-altitude populations in the rarefied air of the high mountains. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. K.D.O.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. B.T.M.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. None. Due to restriction in the number of articles that can be cited in this Perspective, not all relevant literature is cited. Additional citations informing the narrative on muscle fibre cross-sectional area and capillary to fibre ratio can be found in the peer review report accompanying this article. The authors are grateful to the referee for drawing our attention to these papers. Open access funding provided by IReL.