X-linked myopathy with excessive autophagy: characterization and therapy testing in a zebrafish model
Bibliographic record
Abstract
X-linked myopathy with excessive autophagy (XMEA), a rare childhood-onset autophagic vacuolar myopathy caused by mutations in VMA21, is characterized by proximal muscle weakness and progressive vacuolation. VMA21 encodes a protein chaperone of the vacuolar hydrogen ion ATPase, the loss of which leads to lysosomal neutralization and impaired function. At present, there is an incomplete understanding of XMEA, its mechanisms, consequences on other systems, and therapeutic strategies. A significant barrier to advancing knowledge and treatments is the lack of XMEA animal models. Therefore, we used CRISPR-Cas9 editing to engineer a loss-of-function mutation in zebrafish vma21. The vma21 mutant zebrafish phenocopy the human disease with impaired motor function and survival, liver dysfunction, and dysregulated autophagy indicated by lysosomal de-acidification, the presence of characteristic autophagic vacuoles in muscle fibers, altered autophagic flux, and reduced lysosomal marker staining. As proof-of-concept, we found that two drugs, edaravone and LY294002, improve swim behavior and survival. In total, we generated and characterized a novel preclinical zebrafish XMEA model and demonstrated its suitability for studying disease pathomechanisms and identifying potential therapeutic targets.
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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 | 0.001 |
| 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".