Adaptation is one of the fundamental characteristics of life activities; humans and animals inhabiting high altitudes are well adapted to hypobaric hypoxic environments, and studies on the mechanisms of this adaptation emerged a hundred years ago. Based on these studies, this paper reviews the adaptive changes in hypoxia-sensitive tissues and organs, as well as at the molecular genetic level, such as pulmonary, cardiovascular, O₂-consuming tissues, and the hemoglobin and HIF pathway, that occur in animals in response to the challenge of hypobaric hypoxia. High-altitude hypoxia adaptation may be due to the coordinated action of genetic variants in multiple genes and, as a result, adaptive changes in multiple tissues and organs at the physiological and biochemical levels. Unraveling their mechanisms of action can provide a reference for the prevention and treatment of multiple diseases caused by chronic hypoxia.

The Tibetan sheep is an indigenous species of the Tibetan plateau and has been well adapted to high-altitude hypoxia. In comparison to lowland sheep breeds, the blood gas indicators have changed and the HIFs signaling pathway is activated in Tibetan sheep. These phenotypic and genetic alterations in Tibetan sheep are thought to be an important basis for adaptation to high-altitude hypoxia and variation in genes encoding the subunits that make up HIFs, such as HIF-1α can affect blood gas indicators. In this study, exons 9, 10, 12 of the HIF-1α gene were sequenced to find variations and 3 SNPs were detected, and these 3 SNPs were genotyped by KASP in 341 Hu sheep and 391 Tibetan sheep. In addition, 197 Hu sheep, 160 Tibetan sheep and 12 Gansu alpine merino sheep were used for blood gas indicators analysis. The results showed significant differences between the blood gas indicators of high-altitude breeds (Tibetan sheep and Gansu alpine merino sheep) and low-altitude breeds (Hu sheep), implying that the differences in blood gas indicators are mainly caused by differences in altitude. The haplotype combinations H2H3 and H1H3 were more frequent in the Tibetan sheep population, H2H3 increases O₂ carrying capacity by increasing hematocrit and hemoglobin concentrations; H1H3 makes O₂ dissociate more readily from oxyhemoglobin by decreasing partial pressure of oxygen and oxygen saturation. These results suggest that variants at the HIF-1α promote the ability of oxygen utilization in Tibetan sheep, which may underpin the survival and reproduction of Tibetan sheep on the Tibetan plateau.

The Tibetan sheep is an indigenous animal of the Tibetan plateau, and after a long period of adaptation have adapted to high-altitude hypoxia. Many physiological changes occur in Tibetan sheep as they adapt to high-altitude hypoxia, especially in the lungs. To reveal the physiological changes and their molecular mechanisms in the lungs of Tibetan sheep during adaptation to high altitudes, we selected Tibetan sheep from three altitudes (2500 m, 3500 m, and 4500 m) and measured blood-gas indicators, observed lung structures, and compared lung proteome changes. The results showed that the Tibetan sheep increased their O₂-carrying capacity by increasing the hemoglobin (Hb) concentration and Hematocrit (Hct) at an altitude of 3500 m. While at altitude of 4500 m, Tibetan sheep decreased their Hb concentration and Hct to avoid pulmonary hypertension and increased the efficiency of air-blood exchange and O₂ transfer by increasing the surface area of gas exchange and half-saturation oxygen partial pressure. Besides these, some important proteins and pathways related to gas transport, oxidative stress, and angiogenesis identified by proteome sequencing further support these physiology findings, including HBB, PRDX2, GPX1, GSTA1, COL14A1, and LTBP4, etc. In conclusion, the lungs of Tibetan sheep are adapted to different altitudes by different strategies; these findings are valuable for understanding the basis of hypoxic adaptation in Tibetan sheep.

Tibetan sheep are indigenous to the Qinghai-Xizang Plateau. Owing to the harsh hypoxic environment in this plateau, the hemoglobin (Hb) protein in Tibetan sheep has undergone adaptive changes over time. Hb is primarily responsible for transporting O₂ and CO₂ between the lungs and other tissues of the body. The α subunit of Hb, encoded by the HBA gene, is a crucial component of the protein. However, whether variations in the HBA gene sequence affect the adaptation of Tibetan sheep to high-altitude hypoxia remains unclear. In this study, we sequenced the HBA gene and identified three single nucleotide polymorphisms (SNPs). These SNPs were genotyped in Tibetan and Hu sheep using Kompetitive Allele-Specific PCR (KASP). The results showed that the frequencies of the AT genotype and H1H2 haplotype were higher in Tibetan sheep than in Hu sheep. Individuals with the AT genotype exhibited higher P₅₀ levels, whereas those with the H1H2 haplotype exhibited lower PO₂ and SaO₂ levels. The higher P₅₀ levels indicated that O₂ was more readily released from oxygenated Hb into the tissues, with the lower PO₂ and SaO₂ levels facilitating this process. These findings indicate that variations in the HBA gene sequence contribute to enhancing O₂ transfer efficiency in Tibetan sheep.

Rumen microbiota and metabolites play important roles in energy metabolism and immune regulation in the host. However, the underlying mechanisms of their interaction with the host to regulate yak plateau adaptation remain unknown. In this study, the effects of altitude on the rumen microbiome, metabolome, and fermentation parameters of yaks were analyzed. The fiber content of pasture grasses increased with altitude, while crude protein content was significantly higher at an altitude of 2800 m (T2800) compared to an altitude of 4500 m (T4500) (p < 0.05). The acetic acid, propionic acid, and volatile fatty acids of yaks in the T4500 group were significantly higher than in the T2800 group (p < 0.05). Simpson’s index of rumen microorganisms in the T4500 group of yaks was significantly higher than in T2800 and T3500 yaks. The relative abundance of Rikenellaceae_RC9_gut_group and Succiniclasticum was significantly higher in T4500 than in T2800, while Prevotella and Streptococcus were more abundant in T2800 than in T4500. Rumen metabolomics analyses revealed that yak rumen metabolites at different altitudes were influenced by forage and altitude, mainly affecting energy metabolism and fatty acid biosynthesis (such as purine and glycerophospholipid metabolism). In summary, altitude may influence rumen microbes and metabolites through pasture nutrient composition.

Tibetan sheep, a unique breed indigenous to the Qinghai–Tibet Plateau, exhibit remarkable adaptations to high-altitude hypoxia, and their muscle quality is a key economic determinant. However, the molecular mechanisms by which exercise regulates meat quality in this breed remain poorly understood. This study aimed to systematically investigate the effects of different exercise volumes on the biceps femoris muscle of Tibetan sheep, integrating histological analysis with high-throughput transcriptome sequencing. We compared a low-exercise group with a high-exercise group and found that long-term endurance exercise resulted in phenotypic changes suggestive of a shift toward oxidative muscle fiber characteristics. This adaptation was characterized by significantly reduced muscle fiber diameter and cross-sectional area, alongside a crucial increase in intramuscular fat content, collectively enhancing meat tenderness, flavor, and juiciness. Transcriptomic analysis revealed extensive gene expression reprogramming, identifying 208 mRNAs and 490 lncRNAs that were differentially expressed and primarily associated with muscle fiber transition and energy metabolism. Furthermore, we constructed a putative lncRNA-miRNA-mRNA competing endogenous RNA network based on expression correlations and bioinformatic predictions, highlighting potential key regulatory axes such as LOC105603384/miR-16-z/MYLK3, LOC121820630/miR-381-y/NOX4, and LOC132659150/oar-miR-329a-3p/NF1. These findings provide a new perspective on the molecular basis of exercise-induced muscle adaptation in high-altitude animals and offer a solid theoretical framework for improving meat quality through scientific livestock management.