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.

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.

The extreme environmental conditions of high-altitude regions, particularly hypoxia, pose significant challenges to animal survival. Tibetan sheep serve as an exemplary model for studying mammalian hypoxic adaptation. Skeletal muscle, crucial for movement and energy metabolism, undergoes adaptive restructuring, yet the underlying molecular mechanisms, particularly the role of the competitive endogenous RNA (ceRNA) network, remain poorly understood. This study aimed to investigate the morphological changes in skeletal muscle across different altitudes and elucidate the potential ceRNA-mediated regulatory mechanisms. Our results revealed that Tibetan sheep from Qinghai-Tibet Plateau high-altitude (QH) regions exhibited significantly greater muscle fiber diameter and area in the biceps femoris compared to those from lower altitudes. To explore the underlying molecular mechanisms, a circRNA-miRNA-mRNA ceRNA network was constructed, identifying several potential key regulatory axes. These included novel_circ_003862/miR-2440-z/LPL, novel_circ_015124/miR-20-y/LGR4, and novel_circ_012468/miR-2440-z/E2F6. Notably, the expression of LPL and E2F6 was upregulated, while LGR4 was downregulated in the QH group, suggesting a potential coordinated shift towards glycolytic metabolism to maintain energy supply under hypoxic stress. These findings suggest that hypoxic environments may promote the adaptive remodeling of skeletal muscle fibers by modulating a specific ceRNA network. The altered expression of key genes like LPL, LGR4, and E2F6 potentially enhances glycolytic metabolism to cope with hypoxic stress. This study provides new insights into the molecular genetic basis of high-altitude adaptation in mammals, though experimental validation is required.

This study examines the impact of altitude on skeletal muscle adaptation in Tibetan sheep and the associated molecular mechanisms. A total of fifteen Tibetan sheep were used, with five each at low (L), middle (M), and high (H) altitude. Myofibril diameter, intramuscular fat (IMF) content, and mRNA and lncRNA expression profiles in the biceps femoris were analyzed. Based on this, a competitive endogenous RNA regulatory network in the biceps femoris was constructed. The results indicated that the myofibril diameter in the H group and the IMF content in the L group were significantly greater than those in the other groups (p < 0.05). These phenotypic changes may be associated with a shift towards Type IIx muscle fibers, though direct fiber-type classification requires further validation. Additionally, the expression levels of lncRNAs, such as LOC114116860, LOC132657892, and LOC114117858, were notably up-regulated in the H group. These lncRNAs may alleviate the inhibitory effects on genes such as FOXO1 and TRIM63 by interacting with miR-186-x, miR-4484-z, and oar-miR-23b. These lncRNAs and mRNAs could be involved in biological processes such as muscle fiber type switching and energy metabolism. This research provides valuable insights into the hypoxia adaptation mechanisms of Tibetan sheep and a foundation for exploring the role of lncRNA and mRNA in the regulation of skeletal muscle plasticity under high-altitude conditions.