Calcium plays a vital role in cellular processes, and hypoxia can induce increases in intracellular calcium due to reduced activity of ATP-dependent calcium exporters. However, the extent of hypoxia-induced changes in calcium handling and its downstream effects on physiology in vivo remains unclear. We aim to determine if modified calcium signaling in hypoxia is a key mechanism responsible for shifts in immune function during high-altitude exposure. We hypothesized that acute high-altitude exposure would stimulate cellular calcium sequestration and therefore reduce plasma calcium levels. To test this hypothesis, healthy sea-level residents traveled to high altitude (3800m) for three days, and fasting blood samples were collected at sea level and each morning at high altitude. RNA sequencing was performed on peripheral immune cells (N=15), and expression of calcium-handling genes was evaluated. Plasma calcium levels were also measured in a separate cohort (N=16; randomized placebo-controlled trial, with 8 receiving Acetazolamide and 8 receiving placebo). We found several genes related to calcium handling were differentially expressed at high altitude (21 upregulated, 15 downregulated), including upregulation of calcium transporters RYR1 (adj. p=0.030), RYR2 (adj. p=0.035), and CAV1 (adj. p=0.0030). However, contrary to our hypothesis, plasma calcium levels were elevated after three days at high altitude (ANOVA main effect p=0.026; SL: 4.8±0.98 mg/uL; HA: 5.6±0.77 mg/uL) but did not differ across Acetazolamide and placebo treatments (p=0.32). These results suggest that acute high-altitude exposure alters calcium homeostasis and provides support for a calcium-dependent mechanism of immune cell responses to hypoxia. Funding Sources: Wilderness Medical Society and the Academy of Wilderness Medicine Herbert N. Hultgren Grant to ECH, University of California Natural Reserve System – White Mountain Research Center Mini Grant to AV. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Pagliero et al. (Fri,) studied this question.