Abstract
Tibetan pigs show a widespread distribution in plateau environments and exhibit striking physiological and phenotypic differences from others pigs for adaptation to hypoxic conditions. However, the regulation of mRNAs and metabolites as well as their functions in the alveolar type II epithelial (ATII) cells of Tibetan pigs remain undefined. Herein, we carried out integrated metabolomic and transcriptomic profiling of ATII cells between Tibetan pigs and Landrace pigs across environments with different oxygen levels to delineate their signature pathways. We observed that the differentially accumulated metabolites (DAMs) and differentially expressed genes (DEGs) profiles displayed marked synergy of hypoxia-related signature pathways in either Tibetan pigs or Landrace pigs. A total of 1,470 DEGs shared between normoxic (TN, ATII cells of Tibetan pigs were cultured under 21% O2; LN, ATII cells of Landrace pigs were cultured under 21% O2) and hypoxic (TL, ATII cells of Tibetan pigs were cultured under 2% O2; LL, ATII cells of Landrace pigs were cultured under 2% O2) groups and 240 DAMs were identified. Functional enrichment assessment indicated that the hypoxia-related genes and metabolites were primarily involved in glycolysis and aldosterone synthesis and secretion. We subsequently constructed an interaction network of mRNAs and metabolites related to hypoxia, such as guanosine-3′, 5′-cyclic monophosphate, Gly-Tyr, and phenylacetylglycine. These results indicated that mitogen-activated protein kinase (MAPK) signaling, aldosterone synthesis and secretion, and differences in the regulation of MCM and adenosine may play vital roles in the better adaptation of Tibetan pigs to hypoxic environments relative to Landrace pigs. This work provides a new perspective and enhances our understanding of mRNAs and metabolites that are activated in response to hypoxia in the ATII cells of Tibetan pigs.
Highlights
Tibetan pigs are well adapted to high-altitude environments and primarily live in semi-agricultural and semi-pastoral areas with an average elevation of 2,500–4,300 m on the Qinghai-Tibet Plateau in Southwest China, as an ideal model for investigating the biological mechanisms of hypoxic adaptation (Groenen et al, 2012; Shang et al, 2020)
We examined and integrated the differentially expressed mRNAs (DEGs) and differentially expressed metabolomics (DAMs) for overlapping metabolic pathways performed by two way orthogonal PLS (O2PLS) analysis to identify hypoxia related genes and pathways based on both the metabolome and transcriptome datasets
A total of 1,470 DEGs were identified and screened based on the intersection in ATII cells between normoxic (TN, LN) and hypoxic (TL, LL) groups to explore the potential functions of gene responses in hypoxia, which considered as the most interesting candidates (Figure 2C, Supplementary Material S4)
Summary
Tibetan pigs are well adapted to high-altitude environments and primarily live in semi-agricultural and semi-pastoral areas with an average elevation of 2,500–4,300 m on the Qinghai-Tibet Plateau in Southwest China, as an ideal model for investigating the biological mechanisms of hypoxic adaptation (Groenen et al, 2012; Shang et al, 2020). ATII cells may repair lung damage under hypoxia (Lottes et al, 2014), the effects of O2 limitation on the mRNA and metabolic pathways necessary to maintain cellular energy in ATII cells have not been studied extensively This project aimed to reveal the network and intercellular signal transduction pathways that contribute to energy homeostasis by identifying DEGs and specific metabolic processes via 2D analyses of the transcriptome and metabolome using primary ATII cells of Tibetan pigs cultured in normoxic and hypoxic conditions
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