Aberrant Respiratory Control in the <i>Mdx</i> Mouse Model of Duchenne Muscular Dystrophy
Notice bibliographique
Résumé
Duchenne muscular dystrophy (DMD) is a neuromuscular disease that results in the absence of the dystrophin protein, leading to severe muscle weakness. Although patients suffer from cardio‐respiratory failure, there is a paucity of information regarding the control of breathing in pre‐clinical models of DMD. We measured ventilation, oxygen consumption (VO 2 ) and carbon dioxide production (VCO 2 ) in freely behaving mdx (C57BL/10ScSn‐Dmd mdx /J; n=12) and wild‐type (C57BL/10ScSn; n=13) mice at 8 weeks of age during normoxia (F i O 2 =0.21) and in response to a graded hypoxic challenge (F i O 2 =0.15, 0.12, 0.1 & 0.08). Carotid sinus nerve activity was measured ex vivo in an artificially perfused preparation in WT (n=6) and mdx (n=6) mice during normoxia (Po 2 =100 Torr) and graded hypoxia (Po 2 =80, 60, 40 Torr). Diaphragm EMG was recorded in urethane (1.8 g/kg) anaesthetised WT (n=9) and mdx (n=7) mice during eupnea and in response to chemostimulation (5% CO 2 /15%O 2 ). Diaphragm muscle force‐frequency relationship was examined ex vivo (n=7 per group). qRT‐PCR was used to examine gene expression in diaphragm muscle from WT and mdx (n=8 per group) mice. Data were expressed as mean±SD and were statistically compared by unpaired Student t ‐test or two‐way ANOVA with Bonferroni post‐hoc test. Minute ventilation (V E ) was significantly reduced in mdx mice compared with WT. There was no significant difference in VO 2 and VCO 2 between WT and mdx when expressed in absolute terms. Carotid sinus nerve unitary discharge was significantly depressed during normoxia in mdx compared with WT ex vivo . Chemostimulation increased diaphragm EMG activity in all animals, with mdx displaying significantly enhanced reflex responsiveness to chemostimulation (amplitude and area under curve of integrated EMG signal; % change from baseline). Diaphragm force was significantly reduced in mdx compared with WT across all stimulation frequencies ex vivo . Immunofluorescence for MHC fibre types revealed decreased type 2B and increased type 2A in mdx diaphragm. In addition, mdx diaphragm had significantly increased central nucleation and inflammatory cell infiltration. NF‐kB and TNF‐α mRNA expression were both significantly increased in mdx diaphragm compared with WT. A significant respiratory phenotype presents at a young age in the mdx mouse. Mdx mice hypoventilate during normoxia (decreased V E /VCO 2 ), with evidence of hypo‐activity of the carotid body during normoxia, and impaired force‐generating capacity. We observed unaltered carotid body and ventilatory responsiveness to hypoxia in mdx but enhanced neural activation of diaphragm muscle (EMG) in response to chemostimulation. Mdx diaphragm muscle has severe mechanical dysfunction, is in a pro‐inflammatory state and has altered fibre type composition and distribution. Our data suggest potentiated neural output for a given chemosensory input but this is insufficient to overcome sensory and muscle deficits and therefore hypoventilation prevails. We reveal that respiratory control is altered in the mdx mouse model of DMD at a young age. Support or Funding Information Department of Physiology (UCC) and Muscular Dystrophy Ireland.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».