Abstract 19337: Cathepsin L is Required to Modulate Cardiac Hypertrophy through Activation of the Autophagy-Lysosomal Dependent Protein Processing Pathway
Bibliographic record
Abstract
Background_Autophagy is critical in the maintenance of cellular protein quality control involved in the cell growth, survival and death. Cathepsin L (CTSL) is a key member of the lysosomal protease family that is expressed in the murine and human heart, and may play an important role in dynamic protein control. We hypothesized that CTSL is important in regulating protein processing in the heart, particularly under pathological stress. Methods and Results_Phenylephrine-induced cardiac hypertrophy in vitro was significantly more pronounced in CTSL deficient neonatal cardiomyocytes compared to controls. This was accompanied by a significantly increased accumulation of autophagosomes, increased levels of ubiquitin-conjugated protein, impaired protein degradation and increased cell death. These phenomena were rescued with Ctsl1 replacement via adeno-associated virus mediated gene transfer. In the in vivo murine model of aortic banding (AB), CTSL deficiency (Ctsl-/-) markedly exacerbated cardiac hypertrophy, worsened cardiac function, and increased mortality. Ctsl-/- AB mice demonstrated significantly decreased lysosomal activity, and increased sarcomere-associated protein aggregation. Homeostasis of the endoplasmic reticulum was also altered with increased Bip and GRP94 proteins in Ctsl-/- AB mice, accompanied by increased ubiquitin-proteasome system activity and higher levels of ubiquitinated proteins in response to AB. These changes ultimately led to a decrease in cellular ATP production, enhanced oxidative stress, and increased cellular apoptosis. Conclusions_Lysosomal CTSL is a key contributor to modulate the cardiac response to hypertrophic stress through regulation of protein processing and quality control.
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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 | 0.000 | 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".