Myoblast expansion defects leads to muscle growth delay and subsequent compensatory adaptation in adult Atrx cKO skeletal muscle
Notice bibliographique
Résumé
Background The growth of muscle tissue and its regeneration from injury is crucially dependent on a self-renewing population of muscle progenitor cells called satellite cells. Activated satellite cells give rise to a rapidly expanding population of myoblasts that increase muscle mass by differentiating into new or adding into pre-existing muscle fibers. Patients with mutations in the chromatin remodeling gene ATRX are clinically characterised by severe cognitive disabilities and muscular hypotonia, thus dramatically compromising their independent locomotory ability. Materials and methods We generated a skeletal muscle specific knockout mouse model by interbreeding Myf5-Cre mice with mice harbouring the Atrx floxed conditional knockout allele (herein referred to as Atrx cKO). Body mass of Atrx cKO and control littermates were measured along with general morphometric analysis of select hindlimb muscles at 3weeks, 5-weeks, and greater than 8-weeks of age. Methods of analysis included single muscle fiber preparations from the extensor digitorum longus (EDL) and soleus muscles as well as RNA expression analysis from the EDL and soleus muscles. Primary myoblasts were also cultured from dissociated muscle tissue from the hindlimbs and analyzed via immuno-fluorescent microscopy. Neuromuscular acuity and endurance was assessed in Atrx cKO and control littermates by the roto-rod apparatus. Muscle strength was assessed by utilizing a digital grip strength measuring apparatus. Results Atrx cKO mice presented with telltale characteristics of weaker musculature, exemplified by spinal kyphosis and reduced body mass at 3-weeks of age. Satellite cell derived myoblasts from Atrx cKO mice were incapable of rapid expansion in culture but were fully capable of terminally differentiating. Atrx cKO myoblasts displayed delayed cell cycle progression through mid-late S-phase and rampant signs of genomic instability characterised by fragmented nuclei, g-H2AX foci, and telomeric aberrations. Despite inefficient myoblast proliferative capacity, Atrx cKO animals were able to re-establish normal body mass by adulthood. Muscular fitness and function in Atrx cKO mice was also age dependent, as younger 3-week old Atrx cKO mice had a reduced capacity to stay on the roto-rod and poorer gripping strength. However, differences in grip strength of adult Atrx cKO mice were almost indistinguishable from their control littermates. Data regarding pathways mediating the hypertrophic compensatory adaptation in Atrx cKO mice will also be presented. Conclusions Inefficient expansion of activated satellite cells in Atrx cKO mice results in delayed muscle development up to 3-weeks of age, when myonuclear accretion reaches its plateau. Reduced muscle mass at 3-weeks of age also correlated with poorer performance in physical tasks that require muscular force, endurance, and coordination. Compensatory mechanisms are triggered after 3-weeks of age in Atrx cKO mice that allow for the eventual recovery of body mass and muscle functionality in adults.
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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 | 0,001 | 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».