Fasting promotes acute hypoxic adaptation by suppressing mTOR-mediated pathways

Rapid adaptation to a hypoxic environment is an unanswered question that we are committed to exploring. At present, there is no suitable strategy to achieve rapid hypoxic adaptation. Here, we demonstrate that fasting preconditioning for 72 h reduces tissue injuries and maintains cardiac function, consequently significantly improving the survival rates of rats under extreme hypoxia, and this strategy can be used for rapid hypoxic adaptation. Mechanistically, fasting reduces blood glucose and further suppresses tissue mTOR activity. On the one hand, fasting-induced mTOR inhibition reduces unnecessary ATP consumption and increases ATP reserves under acute hypoxia as a result of decreased protein synthesis and lipogenesis; on the other hand, fasting-induced mTOR inhibition improves mitochondrial oxygen utilization efficiency to ensure ATP production under acute hypoxia, which is due to the significant decrease in ROS generation induced by enhanced mitophagy. Our findings highlight the important role of mTOR in acute hypoxic adaptation, and targeted regulation of mTOR could be a new strategy to improve acute hypoxic tolerance in the body.

HIF1α stabilization in hypoxia is not oxidant-initiated

Hypoxic adaptation mediated by HIF transcription factors requires mitochondria, which have been implicated in regulating HIF1α stability in hypoxia by distinct models that involve consuming oxygen or alternatively converting oxygen into the second messenger peroxide. Here, we use a ratiometric, peroxide reporter, HyPer to evaluate the role of peroxide in regulating HIF1α stability. We show that antioxidant enzymes are neither homeostatically induced nor are peroxide levels increased in hypoxia. Additionally, forced expression of diverse antioxidant enzymes, all of which diminish peroxide, had disparate effects on HIF1α protein stability. Moreover, decrease in lipid peroxides by glutathione peroxidase-4 or superoxide by mitochondrial SOD, failed to influence HIF1α protein stability. These data show that mitochondrial, cytosolic or lipid ROS were not necessary for HIF1α stability, and favor a model where mitochondria contribute to hypoxic adaptation as oxygen consumers.

Whole-Transcriptome Analysis of Yak and Cattle Heart Tissues Reveals Regulatory Pathways Associated With High-Altitude Adaptation

BackgroundThe yak (Bos grunniens) is an important livestock species that can survive the extremely cold, harsh, and oxygen-poor conditions of the Qinghai-Tibetan Plateau and provide meat, milk, and transportation for the Tibetans living there. However, the regulatory network that drive this hypoxic adaptation remain elusive.ResultsThe heart tissues from LeiRoqi (LWQY) yak and their related cattle (Bos Taurus) breeds, which are two native cattle breeds located in high altitude (HAC) and low altitude (LAC) regions, respectively, were collected for RNA sequencing. A total of 178 co-differentially expressed protein-coding transcripts (co-DETs) were discovered in each of the LAC-vs-LWQY and LAC-vs-HAC comparison groups, including NFATC2, NFATC1, ENPP2, ACSL4, BAD, and many other genes whose functions were reported to be associated with the immune-system, endocrine-system, and lipid metabolism. Two and 230 lncRNA transcripts were differentially expressed in the LAC-vs-LWQY and LAC-vs-HAC comparisons’ respectively, but no lncRNA transcripts that were co-differentially expressed. Among the 58 miRNAs that were co-differentially expressed, 18 were up-regulated and 40 were down-regulated. In addition, 640 (501 up-regulated and 139 down-regulated) and 152 (152 up-regulated and one down-regulated) circRNAs showed differential expression in LAC-vs-LWQY and LAC-vs-HAC comparison groups, respectively, and 53 up-regulated co-differentially expressed circRNAs were shared. Multiple co-DETs, which are the targets of miRNAs/lncRNAs, are significantly enriched in high-altitude adaptation related processes, such as, T cell receptor signaling, VEGF signaling, and cAMP signaling. A competing endogenous RNA (ceRNA) network was constructed by integrating the competing relationships among co-differentially expressed mRNAs, miRNAs, lncRNAs and circRNAs. Furthermore, the hypoxic adaptation related ceRNA network was constructed, and the six mRNAs (MAPKAPK3, PXN, NFATC2, ATP7A, DIAPH1, and F2R), the eight miRNAs (including miR-195), and 15 circRNAs (including novel-circ-017096 and novel-circ-018073) are proposed as novel and promising candidates for regulation of hypoxic adaptation in the heart.ConclusionIn conclusion, the data recorded in the present study provides new insights into the molecular network of high-altitude adaptation along with more detailed information of protein-coding transcripts and non-coding transcripts involved in this physiological process, the detailed mechanisms behind how these transcripts “crosstalk” with each other during the plateau adaptation are worthy of future research efforts.

Comprehensive analysis of coding and non-coding RNA transcriptomes related to hypoxic adaptation in Tibetan chickens

Background Tibetan chickens, a unique native breed in the Qinghai-Tibet Plateau of China, possess a suite of adaptive features that enable them to tolerate the high-altitude hypoxic environment. Increasing evidence suggests that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play roles in the hypoxic adaptation of high-altitude animals, although their exact involvement remains unclear. Results This study aimed to elucidate the global landscape of mRNAs, lncRNAs, and miRNAs using transcriptome sequencing to construct a regulatory network of competing endogenous RNAs (ceRNAs) and thus provide insights into the hypoxic adaptation of Tibetan chicken embryos. In total, 354 differentially expressed genes (DE genes), 389 differentially expressed lncRNAs (DE lncRNAs), and 73 differentially expressed miRNAs (DE miRNAs) were identified between Tibetan chickens (TC) and control Chahua chickens (CH). GO and KEGG enrichment analysis revealed that several important DE miRNAs and their target DE lncRNAs and DE genes are involved in angiogenesis (including blood vessel development and blood circulation) and energy metabolism (including glucose, carbohydrate, and lipid metabolism). The ceRNA network was then constructed with the predicted DE gene-DE miRNA-DE lncRNA interactions, which further revealed the regulatory roles of these differentially expressed RNAs during hypoxic adaptation of Tibetan chickens. Conclusions Analysis of transcriptomic data revealed several key candidate ceRNAs that may play high-priority roles in the hypoxic adaptation of Tibetan chickens by regulating angiogenesis and energy metabolism. These results provide insights into the molecular mechanisms of hypoxic adaptation regulatory networks from the perspective of coding and non-coding RNAs.

A PAS Protein Directs Metabolic Reprogramming during Cryptococcal Adaptation to Hypoxia

ABSTRACT To aerobic organisms, low oxygen tension (hypoxia) presents a physiological challenge. To cope with such a challenge, metabolic pathways such as those used in energy production have to be adjusted. Many of such metabolic changes are orchestrated by the conserved hypoxia-inducible factors (HIFs) in higher eukaryotes. However, there are no HIF homologs in fungi or protists, and not much is known about conductors that direct hypoxic adaptation in lower eukaryotes. Here, we discovered that the transcription factor Pas2 controls the transcript levels of metabolic genes and consequently rewires metabolism for hypoxia adaptation in the human fungal pathogen Cryptococcus neoformans. Through genetic, proteomic, and biochemical analyses, we demonstrated that Pas2 directly interacts with another transcription factor, Rds2, in regulating cryptococcal hypoxic adaptation. The Pas2/Rds2 complex represents the key transcription regulator of metabolic flexibility. Its regulation of metabolism rewiring between respiration and fermentation is critical to our understanding of the cryptococcal response to low levels of oxygen. IMPORTANCE C. neoformans is the main causative agent of fungal meningitis that is responsible for about 15% of all HIV-related deaths. Although an obligate aerobic fungus, C. neoformans is well adapted to hypoxia conditions that the fungus could encounter in the host or the environment. The sterol regulatory element binding protein (SREBP) is well known for its role in cryptococcal adaptation to hypoxia through its regulation of ergosterol and lipid biosynthesis. The regulation of metabolic reprogramming under hypoxia, however, is largely unknown. Here, we discovered one key regulator, Pas2, that mediates the metabolic response to hypoxia together with another transcription factor, Rds2, in C. neoformans. The findings help define the molecular mechanisms underpinning hypoxia adaptation in this and other lower eukaryotes.

Comprehensive analysis of coding and non-coding RNA transcriptomes related to hypoxic adaptation in Tibetan chickens

Background: Tibetan chickens, a unique native breed in the Qinghai-Tibet Plateau of China, possess a suite of adaptive features that enable them to tolerate the high-altitude hypoxic environment. Increasing evidence suggests that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play roles in the hypoxic adaptation of high-altitude animals, although their exact involvement remains unclear.Results: This study aimed to elucidate the global landscape of mRNAs, lncRNAs, and miRNAs using transcriptome sequencing to construct a regulatory network of competing endogenous RNAs (ceRNAs) and thus provide insights into the hypoxic adaptation of Tibetan chicken embryos. In total, 354 differentially expressed genes (DE genes), 389 differentially expressed lncRNAs (DE lncRNAs), and 73 differentially expressed miRNAs (DE miRNAs) were identified between Tibetan chickens (TC) and control Chahua chickens (CH). GO and KEGG enrichment analysis revealed that several important DE miRNAs and their target DE lncRNAs and DE genes are involved in angiogenesis (including blood vessel development and blood circulation) and energy metabolism (including glucose, carbohydrate, and lipid metabolism). The ceRNA network was then constructed with the predicted DE gene-DE miRNA-DE lncRNA interactions, which further revealed the regulatory roles of these differentially expressed RNAs during hypoxic adaptation of Tibetan chickens.Conclusions: Analysis of transcriptomic data revealed several key candidate ceRNAs that may play high-priority roles in the hypoxic adaptation of Tibetan chickens by regulating angiogenesis and energy metabolism. These results provide insights into the molecular mechanisms of hypoxic adaptation regulatory networks from the perspective of coding and non-coding RNAs.

HYPOXIC ADAPTATION AND TRAINING: HISTORIC, BIOMEDICAL AND SPORT ASPECTS

The review outlines the milestones in studying the processes of human adaptation to hypoxia, and hypoxic training applications in medicine and sports. Contribution of the Russian science to these investigations is disclosed and literary data on the mechanisms of hypoxic adaptation, models and effectiveness of hypoxic training are summarized. The paper is concluded by discussion of hypoxic training potential in high achievements sports.