Metabolic alterations beyond fatty acid oxidation defects in PPARα null mice hearts
Bibliographic record
Abstract
Subjects with fatty acid oxidation (FAO) defects develop a cardiomyopathy, yet the underlying mechanism is unclear. Using our established working mouse heart model and 13C-methodology, we compared the metabolic and functional response of hearts from PPARα null mice, a model of FAO defect, and control C57BL/6 mice at two workloads. Compared to controls, perfused hearts from PPARα null mice depicted functional parameters similar to controls at 12 mmHg preload, but displayed an impaired response to a raise in preload as reflected by a 20% decline in aortic flow and cardiac efficiency, and enhanced MVO2 (20%) and lactate dehydrogenase release (2-fold) (p<0.05). At the metabolic level, these hearts showed the expected shift from FA (4-fold down) to carbohydrate (CHO: 2-fold up; P<0.001), yet flux through anaplerotic pyruvate carboxylation (PC) expressed relative to citric acid cycle (CAC) or pyruvate decarboxylation (PDC), as well as CAC intermediate levels, were similar to controls at both preloads. However, glycolytic rates, expressed as absolute values or relative to PDC were differentially affected by preloads, suggesting a potential mismatch between cytosolic and mitochondrial CHO metabolism in PPARα null mice hearts. Interestingly, when clamped in vivo, these hearts showed higher levels of citrate and malate, suggesting additional, yet-to-be identified, factor(s) determining CAC intermediate pool size in vivo. Gene expression analysis revealed no change for PC, but 20% lower propionyl-CoA carboxylase mRNA levels. Collectively, our data highlight metabolic alterations in PPARα null mice hearts, beyond their lower FAO, which may determine their response to increased energy demand. (Supported by NIH & CIHR)
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".