Sex‐Specific Arrhythmias Caused by Cardiac Sodium Channel Na <sub>v</sub> 1.5 Mutation Alters Cardiomyocyte Metabolism
Notice bibliographique
Résumé
Introduction The activation of cardiac Na v 1.5 sodium channels initiates the action potential in the heart to facilitate coordinated contraction. Mutations in Na v 1.5 disrupts the action potential leading to arrhythmic diseases which increases the risk of sudden cardiac arrest. The gain of function Arg222Gln mutation in Na v 1.5 disrupts structural interactions during channel activation, creating an aberrant pore leading to excessive cations entering the cardiomyocyte (CM). The chronic arrhythmia resulting from Arg222Gln places prolonged stress on the heart which can trigger adverse metabolic reprogramming. We have generated a mouse model possessing the human Arg222Gln mutation where the males illustrate a significant arrhythmia burden, whereas females appear to be protected. We hypothesize that sex‐specifc metabolic reprogramming could provide an explanation for the observed difference in phenotype. Methods The human exon containing the Arg222Gln mutation was knocked into the equivalent mouse locus under the endogenous promoter. Shot‐gun proteomics of total heart lysate was performed using LC‐LC mass spectrometry. Significant proteins were identified with at least two unique peptides and a 5% false discovery rate. Clustering and differentially expressed proteins were analyzed using Metaboanalyst and pathway gene ontological analysis was performed with Cytoscape. Cellular metabolism (oxygen consumption) was measured using isolated adult primary CMs with the Seahorse XFe Analyzer. Results After filtering, mass spectrometry yielded 1654 identified protein across all four analyzed groups (wild‐type and Arg222Gln of both sexes). Unsupervised clustering of the data using principal component analysis and hierarchical clustering revealed complete segregation of the four groups. Sex status contributed most significantly to data segregation, with secondary (but clear) segregation based on Arg222Gln mutation. Comparing Arg222Gln male versus females, there were 157 upregulated proteins and 231 down regulated proteins (P<0.05, ±2‐fold change). Pathway analysis of the differentially expressed proteins reveal multiple changes in metabolic pathways including fatty acid metabolism, pyruvate metabolism, and lactate metabolism. Basal respiration of the isolated CMs in all four groups were unchanged, however maximal respiratory capacity of Arg222Gln males were significantly lower (116.9±13.5pmol O 2 /min, P<0.05) compared to the wild‐type males (407.3±16.4pmol O 2 /min). There were no differences between wild‐type females (451.4±22.4pmol O 2 /min) and Arg222Gln females (463.2±33.7pmol O 2 /min). Conclusion We demonstrate sex‐specific proteomic changes in a mouse model of arrhythmia caused by a gain‐of‐function Na v 1.5 mutation. While there were many perturbed pathways in our analysis, metabolic changes featured prominently. Our data suggests that metabolic reprogramming could play a role in the cardioprotection in females or a compensatory detrimental mechanism in males harboring the Arg222Gln mutation. Future experiments will aim to understand how sex affects cardiac metabolism in the context of Arg222Gln, specifically targeting the specific roles of sex hormones.
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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 ».