Dystrophin‐deficient cardiomyocytes are abnormally vulnerable to mechanical stress‐induced contractile failure and injury
Bibliographic record
Abstract
ABSTRACT Although absence of the cytoskeletal protein dystrophin leads to dilated cardiomyopathy in humans, the functional role of dystrophin in cardiac muscle remains undefined. We have addressed the hypothesis that dystrophin could help protect the heart against injury and contractile dysfunction induced by mechanical stress. In normal and dystrophin‐deficient (mdx) mice, cardiac mechanical stress was first manipulated ex vivo in a perfused working heart preparation. Despite an afterload level in the normal physiologic range, ex vivo perfused mdx hearts developed severe contractile dysfunction and nonischemic tissue damage, as is shown by excessive LDH release without a rise in coronary lactate. Injury to dystrophin‐deficient hearts was significantly correlated with cardiac work, and reducing the afterload level improved contractility and prevented injury in mdx hearts studied ex vivo. The response to mechanical stress in vivo was also assessed by using the vital dye Evans blue, which penetrates into cardiomyocytes with a disrupted sarcolemma. In the mdx group only, cardiomyocyte injury was increased markedly by acute elevations of mechanical stress induced by isoproterenol or brief aortic occlusion. Strikingly accelerated mortality and cardiac necrosis were also observed in the mdx group subjected to chronically increased cardiac mechanical stress via subtotal aortic constriction. Taken together, our results provide the first direct evidence that dystrophin serves to protect cardiomyocytes from mechanical stress and workload‐induced damage. Accordingly, reducing cardiac work in patients with dystrophin deficiency could be beneficial not only in treating established cardiomyopathy, but also in preventing the onset of cardiac disease.
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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) | 0.000 | 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) | 0.001 | 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 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".