Adaptation and acclimatization to high altitude in rodents.

点击翻译按钮获取中文摘要

Mammals living at high altitude (HA) have genetic adaptations to enhance transport and utilization of O2. Over the past centuries, lowland human migrants have established new settlements and introduced new mammalian species to HA. For most of these populations adaptation is an ongoing process, with divergent successes. As an example, rats and mice have both been introduced in South America in the past centuries, but only mice have colonized the HA regions, while rats remain exclusively a lowland species. In line with the phylogeographic history placing the origin of mice around the high-mountain ranges of Asia, we proposed that mice are "pre-adapted" to HA. Over the past few years, we have described the physiological basis underlying these adaptations in mice: elevated ventilation and metabolic rate, large lungs with large exchange surface area, and low levels of mitochondrial oxidative stress in the lungs at HA. Preliminary results indicate that during acclimatization to chronic hypoxia for 3 weeks, mice are able to elevate their minute ventilation and metabolic rate, and show dynamic changes of brain mitochondrial respiration, while these responses are clearly blunted in rats. On the long term, the objectives of my research program are to better understand the physiological and cellular basis of adaptation and pre-adaptation to high altitude by comparing responses to chronic hypoxia in rats and mice. Short-term research questions developed in this proposal will test the following hypothesis: - acclimatization to chronic hypoxia involves plasticity of mitochondrial function and metabolic pathways in the brain and liver (that account for 50% of basal metabolic rate in mice). We will assess mitochondrial respiration efficiency (by measuring the ratio of ATP production to O2 consumption), the activity of key metabolic enzymes, and expression of modulators of mitochondrial respiration and transcription factors related to hypoxic and metabolic responses. - Because sex has a predominant effect on acclimatization to HA, and sex-steroids modulate mitochondrial respiration and metabolic functions in adult and newborn mammals, our second objective will be to test the hypothesis that plasticity of mitochondrial respiration efficiency and metabolic pathways during acclimatization to chronic hypoxia are sex-specific in adults and in newborn. On the long term, we will assess the role of ovarian hormones and their receptors on HA adaptations. - HA residency (La Paz, Bolivia) alters mitochondrial respiration efficiency in the brain and liver of newborn and adults rats and mice. We will work with our colleagues from La Paz, Bolivia, at 3,600m to address this hypothesis. These studies provide rich and stimulating challenges for students, who will have to perform demanding technical approaches with state-of the art equipment and understand how their data fits into this fascinating field of research.