Abstract P425: Sirtuin 3 Attenuates Doxorubicin Induced Cardiac Dysfunction By Regulating The Mitochondrial Acetylome And Alterations Of The Cardiac Lipidome
Bibliographic record
Abstract
Doxorubicin (DOX) is a chemotherapeutic with dose-dependent cardiotoxic effects that limits its use in patients. Previously we showed that DOX decreases expression of the mitochondrial lysine deacetylase SIRT3 in the mouse heart. We hypothesize that DOX impairs cardiac function and energy production through reduced SIRT3 and altered mitochondrial acetylation. We further hypothesize that increased SIRT3 expression could attenuate DOX-induced cardiac dysfunction via alterations of protein acetylation to enzymes involved in lipid remodeling and metabolic processes. Mice expressing cardiac restricted full length M1-SIRT3 (mitochondrial localized), and short M3-SIRT3 (lacking localization signal) received saline or DOX injections of 8 mg/kg body weight for 4 weeks and compared to non-transgenic (Non-Tg) littermates. Transthoracic echocardiography was performed on all mice (n=10). Total cardiac lipids were isolated from DOX treated cardiac tissue by chloroform:methanol extraction and global lipid analysis was performed by QTRAP LC-MS/MS (n=6). Cardiac mitochondria were and an anti-acetylated lysine antibody was used to enrich for tryptic digested peptides containing Acetyl-K and analyzed by QTRAP LC-MS/MS (n=6). In non-Tg mice, DOX caused cardiac dysfunction and expression of M1-SIRT3 and M3-SIRT3 transgenes in the heart preserved left ventricular posterior wall thickness (P<0.05) and ejection fraction (P<0.05) in DOX treated mice. Triglycerides and phospholipids (PE, PI, PC) were decreased in DOX treated mouse hearts while phosphatidylserine (PS), sphingomyelin and ganglioside (GM3) lipid species were increased (p<0.05). A negative correlation between decreased cardiac output and increased GM3 24:1 (R=-0.62, P<0.05), PS 38:4 levels (R=-0.81, P<0.005) and SM 35:1 (R=-0.65, P<0.05) was identified. 36 acetylated peptides involved in metabolic processes, oxidative stress resistance and lipid remodeling (eg. IDH2, SOD2, HADHA, P<0.05) were significantly altered in DOX-treated mice. Increased SIRT3 expression in the heart rescues DOX-induced cardiac dysfunction. DOX-induced cardiac dysfunction involved alterations in cardiac lipids and acetylated proteins that could be rescued by increased SIRT3 expression in the heart.
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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) | 0.001 | 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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".