Distinct Early Signaling Events Resulting From the Expression of the PRKAG2 R302Q Mutant of AMPK Contribute to Increased Myocardial Glycogen
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Bibliographic record
Abstract
BACKGROUND: Humans with an R302Q mutation in AMPKgamma(2) (the PRKAG2 gene) develop a glycogen storage cardiomyopathy characterized by a familial form of Wolff-Parkinson-White syndrome and cardiac hypertrophy. This phenotype is recapitulated in transgenic mice with cardiomyocyte-restricted expression of AMPKgamma(2)R302Q. Although considerable information is known regarding the consequences of harboring the gamma(2)R302Q mutation, little is known about the early signaling events that contribute to the development of this cardiomyopathy. METHODS AND RESULTS: To distinguish the direct effects of gamma(2)R302Q expression from later compensatory alterations in signaling, we used transgenic mice expressing either the wild-type AMPKgamma(2) subunit (TGgamma(2)WT) or the mutated form (TGgamma(2)R302Q), in combination with acute expression of these proteins in neonatal rat cardiomyocytes. Although acute expression of gamma(2)R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content, AMPK activity, glycogen synthase activity, and AS160 expression are reduced in hearts from TGgamma(2)R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, gamma(2)WT expression has similar, yet less marked effects than gamma(2)R302Q expression in both cardiomyocytes and hearts. CONCLUSIONS: Using acute and chronic models of gamma(2)R302Q expression, we have differentiated the direct effects of the gamma(2)R302Q mutation from eventual compensatory modifications. Our data suggest that expression of gamma(2)R302Q induces AMPK activation and the eventual increase in glycogen content, a finding that is masked in hearts from transgenic adult mice. These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it