The Effect of Skeletal Muscle AMPK on the Regulation and Localization of the Dystrophin‐Associated Protein Complex
Bibliographic record
Abstract
The dystrophin‐associated protein complex (DAPC) is composed of proteins that are highly expressed along the sarcolemma. The DAPC provides a mechanical link between the intracellular cytoskeleton and extracellular matrix. Additionally, increasing evidence shows the importance of the DAPC as a mechanosensor and signal transducer across the sarcolemma. The signalling molecule AMP‐activated protein kinase (AMPK) is a powerful regulator of phenotypic plasticity. Chronic pharmacological AMPK stimulation induces the expression of DAPC components, whereas reduced AMPK activity results in DAPC dysfunction. However, a more comprehensive understanding of the influence of AMPK on the DAPC is lacking. Therefore, the purpose of this study was to investigate the role of AMPK in the expression of the DAPC in skeletal muscle. Extensor digitorum longus (EDL) and soleus (SOL) muscles representing fast glycolytic and slow oxidative tissues, respectively, were obtained from wild‐type (WT) mice, as well as from mice deficient in both isoforms of the AMPK‐β subunit in skeletal muscle (AMPK‐MKO). Immunofluorescence imaging was performed to measure the expression and localization of DAPC components dystrophin, β‐dystroglycan (β‐DG), γ‐sarcoglycan, (γ‐SG), neuronal nitric oxide synthase (nNOS), and laminin. β‐DG content was found to be ~2.2‐fold higher (p < 0.05) in SOL compared to EDL muscles from WT animals. However, this fiber type difference was not seen in the muscles from AMPK‐MKO mice. The expression of nNOS was significantly higher (+86%) in the SOL relative to the EDL muscles in AMPK‐MKO animals. This fiber type specificity was not observed in WT mice. The levels of dystrophin, γ‐SG, and laminin were similar between muscle types in both WT and AMPK‐MKO mice, and all DAPC components were similar between genotypes. We next investigated potential regulators of DAPC transcription, including myogenin and myoD. Western blot analyses revealed that the expression of both myogenin and myoD were downregulated by 40–60% (p < 0.05) in EDL and SOL muscles from AMPK‐MKO versus WT mice, which suggests that alternative factors may be contributing to the similar level of DAPC expression between genotypes. Indeed, computational analysis of the 3′ untranslated regions of DAPC components revealed multiple regulatory elements that have been shown to affect mRNA stability in skeletal muscle, such as binding sites for RNA‐binding proteins AUF1, HuR, and KSRP, as well as for microRNAs. Our results suggest that the absence of AMPK in skeletal muscle initiates a compensatory cascade of events at multiple levels of gene expression that coordinate to maintain basal levels of DAPC expression. Thus, although chronic AMPK activation induces DAPC content in skeletal muscle, it appears that AMPK is not essential for the maintenance of DAPC expression. Support or Funding Information Natural Science and Engineering Research Council Canadian Research Chairs
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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) | 0.002 | 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".