Scleraxis is Required for Induction of GLS1 Expression in Cardiac Myofibroblasts
Bibliographic record
Abstract
Cardiac fibrosis is an aberrant wound healing process involving excessive production of extracellular matrix proteins resulting in impaired systolic and diastolic function of the heart, contributing to heart failure and death. Glutaminolysis, which involves conversion of glutamine to glutamate by glutaminase (GLS), and conversion of glutamate to α‐ketoglutarate to fuel oxidative metabolism via the tricarboxylic acid cycle, has been reported as a mechanism for meeting the energy demand required for pulmonary and liver fibrosis however its contribution in cardiac fibrosis is unclear. Although the role of the transcription factor Scleraxis has been established in the phenotypic conversion of cardiac fibroblasts to fibrotic myofibroblasts by our lab, Scleraxis’ role in glutaminolysis remains unelucidated. Our results here show Scleraxis expression was increased by 9 fold and GLS1 by 4 fold when comparing freshly isolated rat cardiac fibroblasts to fibrogenic myofibroblasts. While Scleraxis overexpression increased GLS1 expression 20‐fold, Scleraxis knockdown attenuated GLS1 expression by 76% in cardiac myofibroblasts while cardiac fibroblasts from Scleraxis knockout mice exhibited a 90% loss of GLS1 expression. TGFβ, one of the primary inducers of cardiac fibrosis induces enhanced expression of Scleraxis and has been found to be highly dependent on Scleraxis for many of its downstream effects. TGFβ treatment of activated cardiac fibroblasts from wild type mice doubled the expression of GLS1, but failed to induce GLS1 expression in Scleraxis knockout cells. Via luciferase assay we found a dose‐dependent transactivation of the human GLS1 promoter by Scleraxis in NIH3T3 fibroblasts. While Scleraxis significantly transactivated the hGLS1 promoter, mutation of an E‐Box Scleraxis putative binding site caused 70% attenuation of promoter transactivation. These findings suggest that Scleraxis is sufficient and required to regulate GLS1 expression to facilitate increased energy metabolism during cardiac fibroblast to myofibroblast conversion.
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How this classification was reachedexpand
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 | 0.000 |
| 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 | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".