HIF‐1 plays a key signaling role in physiological responses to acute hypoxia in the African naked mole rat, Heterocephalus glaber
Bibliographic record
Abstract
Naked mole rats are among the most hypoxia‐tolerant mammals identified. This tolerance is partially achieved by their ability to coordinately reduce metabolic and ventilatory rates by > 85% in acute hypoxia. Our understanding of the physiological mechanisms that enable their hypoxia‐tolerance is improving; however, the cellular mechanisms that mediate these responses remain poorly understood. Hypoxia‐inducible factor‐1α (HIF‐1α) is a transcription factor that is central to hypoxic signaling at the cellular level. In most mammals, HIF‐1α is degraded in normoxia but is stabilized when oxygen levels are reduced. Stabilization of HIF‐1α leads to upregulation of a multitude of genes that promote survival in hypoxia. A recent analysis of the naked mole rat genome revealed several mutations to HIF‐1α. These mutations are predicted to prevent HIF‐1α degradation during normoxia, which would chronically upregulate HIF‐1α‐mediated signaling pathways. We hypothesized that endogenous activation of HIF‐1α‐mediated signaling contributes to the remarkable hypoxia‐tolerance of naked mole rats by modulating their metabolic rate. To test our hypothesis, we used pharmacological tools to manipulate HIF‐1α expression in naked mole rats and mice and measured metabolic and ventilatory responses to an acute hypoxic challenge (7% O 2 for 1hr) in awake and unrestrained subjects using plethysmography and respirometry. Pharmacological manipulation of HIF‐1α expression was confirmed by measuring changes in the expression of several downstream gene targets of HIF‐1α. In naked mole rats, blocking HIF‐1α had only minor effects on ventilation but drastically blunted the hypoxic metabolic response. As a result, the naked mole rat air convection requirement (ACR) increased 2‐fold in normoxia and 3‐fold in hypoxia, indicating that naked mole rats were hyperventilating and thus less tolerant of hypoxic stress. Conversely, activating HIF‐1α in mice reduced ventilation and metabolic rate in both normoxia and hypoxia and also reduced the hypoxic increase in the murine ACR, indicating that HIF‐1α‐agonist‐treated mice were more tolerant of hypoxic stress. We conclude that endogenous upregulation of HIF‐1α signaling contributes to the hypoxia‐tolerance of naked mole rats, and we demonstrate that this mechanism can be translated to hypoxia‐intolerant mice to induce a hypoxia‐tolerant phenotype. Support or Funding Information Natural Sciences and Engineering Research Council of Canada, Canada Research Chairs Program, Parker B Francis Foundation
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".