Modulation of the Acetylcholine Receptor Clustering Pathway Improves Neuromuscular Junction Structure and Muscle Strength in a Mouse Model of Congenital Myasthenic Syndrome
Bibliographic record
Abstract
Introduction: Congenital myasthenic syndromes (CMS) are a diverse group of inherited neuromuscular disorders characterized by a failure of synaptic transmission at the neuromuscular junction (NMJ). CMS often present early with fatigable weakness and can be fatal through respiratory complications. The AGRN gene is one of over 30 genes known to harbor mutations causative for CMS. In this study, we aimed to determine if a compound (NT1654), developed to stimulate the acetylcholine receptor (AChR) clustering pathway, would benefit a mouse model of CMS caused by a loss-of-function mutation in Agrn (Agrnnmf380 mouse). Methods:Agrnnmf380 mice received an injection of either NT1654 or vehicle compound daily, with wild-type litter mates used for comparison. Animals were weighed daily and underwent grip strength assessments. After 30 days of treatment animals were sacrificed, and muscles collected. Investigations into NMJ and muscle morphology were performed on collected tissue. Results: While minimal improvements in NMJ ultrastructure were observed with electron microscopy, gross NMJ structure analysis using fluorescent labelling and confocal microscopy revealed extensive postsynaptic improvements in Agrnnmf380 mice with NT1654 administration, with variables frequently returning to wild type levels. An improvement in muscle weight and myofiber characteristics helped increase forelimb grip strength and body weight. Conclusions: We conclude that NT1654 restores NMJ postsynaptic structure and improves muscle strength through normalization of muscle fiber composition and the prevention of atrophy. We hypothesize this occurs through the AChR clustering pathway in Agrnnmf380 mice. Future studies should investigate if this may represent a viable treatment option for patients with CMS, especially those with mutations in proteins of the AChR clustering pathway.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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 | 0.001 |
| 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".