Characterizing the effects of heterozygous neurogranin deletion on myosin heavy chain and calcineurin expression in the murine unloaded soleus
Notice bibliographique
Résumé
Background Neurogranin (Ng) is a small IQ motif protein that binds to the C‐terminal on CaM limiting its cellular availability and sequestering it away from its downstream targets such as calcineurin. Calcineurin is a Ca 2+ /calmodulin (CaM)‐dependent protein that promotes the slow oxidative fibre phenotype in skeletal muscle as well as myoblast fusion. Recent research from our lab shows that Ng is expressed in skeletal muscle, particularly in slow‐oxidative muscles such as the soleus. The soleus is a postural muscle that acts to withstand the downward pull of gravity and unloading the soleus muscle leads to muscle atrophy and a slow‐to‐fast fibre type shift. However, activating calcineurin can attenuate the muscle atrophy and fibre type transition that occurs with soleus unloading. In the present study, we determined the effects of heterozygous Ng deletion on muscle mass and myosin heavy chain (MHC) isoform expression in the unloaded soleus. We hypothesized that lowered Ng expression would enhance calcineurin signaling thereby minimizing muscle atrophy and the slow‐to‐fast fibre type shift. Methods To this end, 3‐4 month‐old male wild‐type (WT) (n=6) and Ng +/‐ (n=8) mice were subjected to tenotomy surgery, where the soleus and gastrocnemius tendons were severed. Soleus muscles were collected two weeks post‐surgery for Western blotting to examine differences in MHC I, IIa, and calcineurin content. Results Soleus to bodyweight ratio was significantly reduced in the unloaded/tenotomy group for both WT (‐55%) and Ng +/‐ mice (‐51%) compared with their respective sham controls ( p <0.001). Western blot analyses revealed that tenotomy‐induced unloading significantly lowered MHC I (‐60%, p =0.03) and MHC IIa (‐63%, p= 0.0001) content, while increasing calcineurin levels (1.4‐fold, p =0.003). However, these effects were blunted in the Ng +/‐ mice with only a 43% reduction in MHC I ( p =0.01), 40% reduction in MHC IIa ( p =0.01), and a non‐significant change in calcineurin (1.0‐fold, p =0.98). Two‐way ANOVA analyses revealed a significant interaction (genotype x tenotomy) for MHC IIa ( p =0.01) and calcineurin ( p =0.007) inidicating that WT mice were more impacted by tenotomy‐induced soleus unloading. Conclusions Our results show that heterozygous Ng deletion did not reduce the muscle atrophy observed with soleus unloading. However, with respect to MHC isoform expression, Ng +/‐ mice were less impacted by unloading with only 40‐43% reductions in MHC I and IIa. This could suggest a blunted slow‐to‐fast fibre type shift. Interestingly, calcineurin was significantly upregulated in the unloaded WT soleus, which we believe is a compensatory response elicited to combat the effects of tenotomy. However, this response was completely absent in the Ng +/‐ mice, perhaps due to sufficient activation of calcineurin with lowered Ng content. In conclusion, this study shows that Ng +/‐ mice respond differently to soleus unloading compared with WT mice.
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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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».