Abstract 3470: Deletion of Glycogen Synthase Kinase-3α (GKS-3α) Causes a Glycogen Storage Cardiomyopathy
Bibliographic record
Abstract
Background: GSK-3 and its targets play critical roles in a wide array of processes including development and cancer. In mammalian cells there are two isoforms, α and β. GSK-3β is purported to be a negative regulator of cardiac hypertrophy, but this is based solely on over-expression approaches, and virtually nothing is known of the functions of GSK-3α. Methods: We generated mice deleted for GSK-3α. Heart development, as well as postnatal cardiac growth, glycogen metabolism, morphology, physiology, and ECG conduction invervals were examined. Age-matched wild type (WT) mice served as controls. Results: Heart development was normal, consistent with full compensation by GSK-3β for loss of GSK-3α during development. However, echocardiographic LV mass (in mg) was significantly increased in the KO compared to WT: 187.95 ± 35.05 vs 143.52 ± 23.94*. Heart weight (HW, mg) and HW/body weight ratio were also significantly increased in the KO: 186.73 ± 15.3* and 4.96 ± 0.38* for KO (n = 19); 146.33 ± 14.92 and 4.12 ± 0.27 for WT (n = 10). Thus deletion of GSK-3α leads to significant cardiac hypertrophy with aging. The underlying mechanism appears to be marked glycogen deposition seen with both Periodic acid-Schiff staining and transmission electron microscopy. Although LV function as assessed by echocardiography was normal at 4 months of age, invasive hemodynamic evaluation demonstrated a depressed response to isoproterenol infusion. ECG revealed a significantly shortened PR interval without pre-excitation. Conclusions: We demonstrate for the first time a striking isoform-specific role for GSK-3α in the heart, and that role is as a critical regulator of glycogen metabolism. Deletion of GSK-3α leads to a glycogen storage cardiomyopathy, sharing some features with that seen with mutations in AMP-activated protein kinase. These data suggest the possibility that mutations in, or alterations in activity of, GSK-3α could account for some cases of hypertrophic cardiomyopathy. (*, P < 0.01, KO vs. WT)
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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 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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".