Abstract 11800: Inhibition of Pyruvate Dehydrogenase Kinase Does Not Improve Cardiac Abnormalities in a Mouse Model of Human Barth Syndrome
Bibliographic record
Abstract
Introduction/Hypothesis: Heart failure presents as the leading cause of infant mortality in individuals with the rare genetic disease, Barth Syndrome (BTHS). The causative mutation underlying the BTHS phenotype has been mapped to the tafazzin ( TAZ) g ene, which encodes for a phospholipid transacylase critical for the remodelling of the mitochondrial phospholipid, cardiolipin. Perturbations in myocardial energy metabolism may contribute to the development and progression of cardiomyopathy in BTHS. Given that cardiac glucose oxidation is impaired in a mouse model of human BTHS, we hypothesized that pharmacological enhancement of glucose oxidation through dichloroacetate (DCA) treatment could mitigate BTHS-related cardiac dysfunction. Methods: DCA was added to the drinking water (84 mM) of 6-week-old mice with experimental BTHS (doxycycline-inducible Taz knockdown (TazKD) mice) for 6-weeks. In vivo cardiac function was assessed via ultrasound echocardiography prior to and following the DCA treatment period. Hearts were extracted from TazKD mice and their wild-type (WT) littermates for protein expression profiling and enzyme activity assessment at the end of the treatment protocol. Results: Prior to treatment at 4-5 weeks of age, TazKD mice exhibited hypertrophic cardiomyopathy as demonstrated by an increase in the ratio between left ventricular (LV) anterior and posterior wall thickness during diastole in relation to lean body mass (0.042±0.003 vs 0.062±0.008 mm/g; 0.049±0.002 vs 0.069±0.005 mm/g). TazKD mice also exhibited impaired LV systolic and diastolic volumes. Treatment with DCA decreased inhibitory phosphorylation of pyruvate dehydrogenase, the rate-limiting enzyme of glucose oxidation, and trended to increase its activity ( p =0.19) in ventricular extracts from TazKD mice compared to their WT littermates, thus suggestive of increased myocardial glucose oxidation. However, despite a potential improvement of cardiac energy metabolism, treatment with DCA did not improve cardiac structural and functional parameters in TazKD mice. Conclusions: Our findings suggest that optimization of cardiac glucose oxidation may not be a feasible strategy for alleviating BTHS-associated cardiomyopathy.
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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 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".