Alterations in the neuromuscular junction proteome with aging
Bibliographic record
Abstract
Denervation has remained a principal factor of age-related muscle atrophy since a report noted significant changes in the end plate morphology at the aged neuromuscular junction [1]. The mechanisms behind the impaired/failed reinnervation and increased denervation seen in aging muscle are not fully understood; however evidence points to an increase in the destabilization of the neuromuscular junction (NMJ). We hypothesized that alterations in the proteome of the NMJ are the primary factors driving the age-associated degeneration and destabilization of the NMJ leading to the impaired/failed reinnervation and increased denervation. Our study utilized Fisher 334 x Brown Norway F1-hybrid rats at an age associated with a striking degree of muscle atrophy [2-4]. We collected NMJ containing muscle fiber segments using laser capture microdissection from 9 young adult (YA) and 9 senescent (SEN) rats. We also used the Sarco mouse as a model of sporadic denervation to separate the effects of denervation from aging. LC-MS/MS analysis revealed both increases and decreases in protein abundances at the aged NMJ. Four and a half lim domains protein 1 was the most overall up-regulated protein at the SEN NMJ and has been linked to Wnt3a which inhibits rapsyn expression and negatively regulates AChR clustering. The intermediate filament desmin and the ECM components decorin and prolargin were all up-regulated at the SEN NMJ and can be classified as specific to aging, potentially as a result of failed reinnervation. We hypothesize that increases in the intermediate filaments and the ECM may be a consequence of long-term denervation and an attempt to overcome the failed reinnervation that occurs with age by providing a stable anchor for AChRs and re-modeling the ECM to attract regenerating axons. Overall, our results agree with the idea that the etiology of sarcopenia is multifactorial. The proteins identified in our experiment provide insights into potential new mechanisms that contribute to the instability of the NMJ and/or failed reinnervation observed in aging muscle.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".