The Effect of Skeletal Muscle AMPK on the Regulation and Localization of the Dystrophin‐Associated Protein Complex
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».