Physiological Differences Underlying Divergent Hypoxia Responses and Altitude Adaptations in Humans, Rats and Mice

Hypobaric hypoxia, a defining feature of high‐altitude environments, poses a considerable physiological challenge to both humans and rodents. To withstand hypoxic stress, mammals have developed cellular and systemic adaptations that not only safeguard against acute and future episodes of oxygen deprivation but may also enhance overall resilience and functional capacity. A central aim of current research is to harness these health‐promoting effects of hypoxic exposure as a therapeutic strategy for a range of medical conditions. To date, much of the evidence regarding the safety and efficacy of such interventions derives from rodent studies. In this review, we summarize current knowledge on hypoxia tolerance, oxygen transport, and oxygen consumption in humans, rats, and mice, and evaluate the extent to which findings from rodent models can be extrapolated to humans. While the anatomical, physiological, and molecular foundations of oxygen transport and utilization are broadly conserved across species, there are important quantitative differences—largely linked to body‐mass variation—as well as qualitative distinctions. Mice that evolved in high‐altitude environments, display remarkable hypoxia tolerance. Their physiological repertoire includes highly efficient pulmonary gas exchange, metabolic downregulation, and substantial plasticity of the mitochondrial electron transport system under hypoxic conditions. In contrast, rats exhibit heightened vulnerability in hypoxia, manifesting as right ventricular hypertrophy, excessive erythropoiesis, and myocardial injury. These interspecies differences highlight that the robust hypoxia tolerance of mice—and the potentially comparatively greater susceptibility of rats than humans—must be carefully considered when translating findings from rodent hypoxia research into human contexts.