Abstract 4361033: Cardiac RBFOX1 Deficiency Enhances Glucose and Ketone Metabolism and Provides Tolerance Against Ischemia Reperfusion Injury
Bibliographic record
Abstract
Introduction: Hibernation or aestivation involve physiologic and molecular adaptations across species that enhance survival under extreme conditions. These include reduced respiratory or heart rate and blood flow, resembling an ischemic state, but without any significant tissue damage. Similarly, the neonatal heart also exhibits protective adaptations against ischemia-reperfusion injury (IRI), resembling hibernation/aestivation. In contrast, adult non-hibernating mammals poorly tolerate ischemia-reperfusion, partly due to excess lactate and H + from anaerobic glycolysis, accelerating ATP depletion used to maintain intracellular pH, resulting in poor cardiac function. Hypothesis: We hypothesized that loss of the cardiac maturation RNA splicing factor RBFOX1 could promote a less mature (neonatal-like) cardiomyocyte state in adult mice, mimicking molecular changes seen during hibernation/aestivation, improving tolerance to IRI. Methods: We used the Alberta snail as a model for hibernation/aestivation and both male and female heart-specific RBFOX1 deficient mice to assess molecular signalling, along with IRI, utilizing the ex-vivo Langendorff working heart model with radiolabelled substrates to measure metabolic alterations. Results: We found increased circulating ketones in the hemolymph of aestivating snails, as well as decreased RBFOX1 levels and markers of less mature cardiomyocytes (i.e., decreased Hoxb13 and Meis1) in snail tissue. RBFOX1 deficient mice had normal cardiac function, but less mature cardiomyocytes, characterized by sarcomere disassembly, stemness marker expression, and increased mono-nucleated cardiomyocytes. Furthermore, RBFOX1-deficient cardiomyocytes had increased levels of glycolytic, ketone oxidation, and fatty acid oxidation rate-limiting enzymes as well as increased L-type Ca 2+ channels and sodium-hydrogen exchangers. These molecular metabolic changes resulted in an increase in baseline glycolysis rates for RBFOX1-deficient hearts, while after 20 minutes of global ischemia they had improved cardiac work recovery and increased post-IR glycolysis and ketone oxidation rates, while fatty-acid oxidation and glucose oxidation rates remained similar to control hearts. Conclusions: Loss of RBFOX1 appears to be an evolutionarily conserved mechanism in aestivating snails and non-hibernating neonatal mice that allows for improved tolerance to IRI through increased glycolysis, ketone oxidation and H + clearing in non-hibernating adult mice.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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".