Skeletal Muscle‐Specific Deletion of AMPKβ1β2 Modulates Age‐Induced Neuromuscular Junction Remodeling in Fast Glycolytic Muscles
Bibliographic record
Abstract
The neuromuscular junction (NMJ) is the electrochemical signaling apparatus between an ⍺‐motoneuron and the skeletal muscle fibers that it innervates. AMP‐activated protein kinase (AMPK) regulates neuromuscular phenotype. However, the precise role of this kinase at the NMJ has yet to be elucidated. The purpose of the current study was to examine the role of skeletal muscle AMPK on NMJ biology across the lifespan. We utilized 3‐ and 12‐month‐old (mo) skeletal muscle‐specific AMPKβ1β2 knock out (mKO, n = 10) and wild‐type (WT, n = 10) mice, as well as 22 mo WT ( n = 3) animals. The extensor digitorum longus (EDL) and soleus (SOL) muscles were examined to represent fast glycolytic and slow oxidative tissues, respectively. Utilizing confocal microscopy, we acquired 20‐25 NMJ images per muscle to conduct 3D NMJ morphology analyses. Contralateral EDL and SOL muscles were also collected for immunofluorescence staining and muscle innervation determination. Quantitative real‐time PCR was employed to examine genes critical for NMJ maintenance and remodeling in tibialis anterior (TA) muscles. Presynaptic axonal blebbing and sprouting was observed more frequently (p < 0.05) in the EDL and SOL muscles of aged WT animals relative to their younger counterparts. Additionally, the proportion of dysmorphic axons was greater (p < 0.05) in mKO animals compared with age‐matched WT mice. As expected, there was a significant main effect of age on the total number of fragmented and ectopic NMJs in both genotypes. mKO animals displayed a greater (p < 0.05) number of dysmorphic NMJs than their age‐matched WT littermates, which suggests that AMPK is required for the development and maintenance of NMJ structure. Indeed, the number of NMJs positive for postsynaptic abnormalities in the EDL muscles of 12 mo mKO animals was significantly greater than 22 mo WT mice. Fiber type grouping was significantly higher in EDL and SOL muscles of 22 mo WT animals relative to their younger counterparts. Statistical trends (p = 0.09) were also observed towards greater fiber type grouping and increased muscle fibers co‐expressing multiple myosin heavy chain isoforms in only the SOL muscles of mKO animals relative to their age‐matched WT controls, which suggests that AMPK elicits muscle‐specific denervation/reinnervation cycling. mRNA expression of the acetylcholine receptor gamma subunit was significantly greater in mKO mice relative to WT animals. Interestingly, additional NMJ transcripts, such as agrin, rapsyn, docking protein 7, and fibroblast growth factor binding protein 1, were significantly lower in mKO animals relative to their WT littermates. Collectively, these data suggest that the absence of skeletal muscle AMPK accelerates age‐associated changes at the NMJ in more glycolytic muscle fibers, potentially due to a greater ability for reinnervation in oxidative muscles. These results reveal a novel role for AMPK in the maintenance and remodeling of the NMJ during aging.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".