Abstract 15562: Loss of Mitochondrial Pyruvate Carrier 1 in Cardiomyocytes Leads to Cardiac Dysfunction and Heart Failure via Hif-1 Activation
Bibliographic record
Abstract
Glucose and lactate are important fuel substrates for the heart, particularly during acute hemodynamic stresses such as pressure overload or following exercise training. Cytosolic pyruvate that is generated by glycolytic metabolism of glucose or by conversion of lactate is transported into mitochondria via the recently described mitochondrial pyruvate carrier complex, which has two subunits, MPC1 and MPC2. The role of pyruvate uptake in regulating cardiac function and metabolism is incompletely understood. Thus, we generated cardiomyocyte-restricted MPC1 knockout mice (CMPC1-/-). Loss of MPC1 resulted in degradation of MPC2 leading to functional inactivation of the MPC complex in CMPC1-/- mouse hearts. Cardiac function examined by echocardiography revealed that CMPC1-/- mice exhibited normal cardiac function by the age of 8 weeks but overt systolic dysfunction was noted at the age of 18 weeks. Survival analysis showed that only 61% of CMPC1-/- mice remained alive at the age of 1year while 98% of control mice survived. At the age of 8 weeks, heart weight (HW) and the heart weight to tibia ratio (HW/TL) were significantly increased, as were characteristic transcriptional markers of pathological cardiac hypertrophy, NPPA, NPPB and Acta1. Substrate metabolism measured in isolated working hearts, revealed a 58% reduction in glucose oxidation in CMPC1-/- mice relative to control mice while palmitate oxidation was increased by 35%. Metabolomics analyses revealed accumulation of pyruvate, lactate and alanine. In contrast, malate and glutamate levels were decreased, suggesting a compensatory increase in malate and glutamate utilization. 2-hydroxyglutarate (2-HG) was also increased in CMPC1-/- mouse hearts, which may activate Hif-1α signaling. Indeed, downstream transcriptional targets of Hif-1 (LDHA, PDK1 and PKM2) were increased. These data suggest that mitochondrial pyruvate uptake although dispensable for normal cardiac development and function in non-stressed juvenile hearts ultimately precipitates pathological cardiac hypertrophy and heart failure in CMPC1-/- mice via 2-HG-mediated Hif-1 activation.
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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) | 0.000 | 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) | 0.006 | 0.002 |
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".