Abstract 310: Mechanistic Insights into Duchenne Muscular Dystrophy-Associated Cardiomyopathy
Bibliographic record
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder resulting from a mutation in the dystrophin gene. Loss of dystrophin function leads to progressive muscle wasting and cardiomyopathy. In 2018, advanced cardiomyopathy is the primary mode of death, despite the application of standard of care CHF therapies. Our group has recently undertaken a cardiac MRI study demonstrating that adult DMD patients have small hearts with very low LV mass as compared to patients with non-ischemic cardiomyopathy or healthy patients. The central hypothesis is DMD-associated cardiomyopathy develops secondary to dysregulation of various cardiac signaling pathways that modulate cardiac growth, namely cardiomyocyte proliferation. Utilizing the mdx mouse, a model of DMD, decreased heart/body weight ratios were noted from birth (P1: Hrt/BW 5.6 ± 0.16 vs. 4.8 ± 0.18 NTg vs mdx p<0.005 n=32). NTg and m dx hearts have similar cardiomyocyte cell size (WGA staining: 0.08 ± 0.001 vs 0.08 ± 0.002 NTg vs mdx p<0.05 n=3), suggesting there are fewer cells in mdx hearts. FACS analysis indicated mdx hearts have fewer cardiomyocytes than NTg hearts (35% reduction; 51.7e 4 ± 4.9e 4 vs. 33.8e 4 ± 3.5e 4 NTg vs mdx p<0.05 n=6). Transcriptome profiling demonstrated that molecular pathways governing cardiac proliferation were significantly reduced in mdx hearts (Ki67: 4.8 ± 0.3 vs 2.0 ± 0.1 NTg vs mdx p<0.005 n=3), with a corresponding increase in cardiac atrophy gene expression at later time points (Foxo3 1.4 ± 0.2 vs 2.8 ± 0.3 NTg vs mdx p<0.005 n=3). Furthermore, immunohistochemical analyses showed significantly reduced proliferation in mdx hearts (Ki67: 13.7 ± 1.2 vs. 6.0 ± 1.0 NTg vs mdx p<0.005, n=3; pH3: 118 ± 5.3 vs 59 ± 4.5 p<0.005 n=3). Finally, RNA-Seq data revealed a disruption of the YAP signaling pathway, an important mediator of cardiomyocyte proliferation, in mdx P4 hearts. Cell cycle targets of YAP were reduced in P4 mdx hearts (20/27 genes, n=3) suggesting a disruption of the Hippo-Yap pathways in mdx hearts. Collectively, the current study provides a unique insight into the mechanism leading to the development DMD cardiomyopathy and directs investigation into potential therapeutic targets for the amelioration of DMD-associated cardiomyopathy.
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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 | 0.001 |
| 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".