Impaired Autophagosome Formation and Autophagy in Skeletal Muscle of Aged American Quarter Horses
Notice bibliographique
Résumé
We have previously reported that mitochondrial function decreased in both gluteus medius ( GM ) and triceps brachii ( TB ) muscle from aged American Quarter Horses; and that activity of the mitochondrial enzyme citrate synthase (CS) in the TB was lower in aged compared to young horses, suggesting a muscle‐specific decrease in mitochondrial content with age (Li et al. 2016 doi: 10.1152/japplphysiol.01077.2015). One underlying cause for the age‐associated decrement of mitochondrial content and function could be an impairment of mitochondrial quality control. Mitochondrial biogenesis and selective degradation of damaged mitochondria (through autophagy) are two of the most prominent quality control mechanisms that have been described. A balance between those two processes is necessary to maintain a healthy population of mitochondria. The objective of the present study was to investigate potential underlying mechanisms that could have caused the age‐associated decline in mitochondrial content and function in equine skeletal muscle by analyzing the expression of factors associated with mitochondrial biogenesis and autophagy pathways. Muscle biopsies of the GM and TB were collected from young (1.8±0.1 yr; n=24) and aged (20±5 yr; n=12) American Quarter Horses, and gene and protein expressions analyzed by qRT‐PCR and immunoblotting. Statistical differences between ages and muscle groups were analyzed using Two‐Way ANOVA and Holm‐Sidak post hoc analysis (Sigmaplot vs. 12.0; Systat Software Inc., San Jose, CA). Consistent with its activity, we found that protein expression of CS was decreased in aged TB ( P <0.05), but not in aged GM . Moreover, mtDNA copy number was decreased with age in TB ( P <0.05) but not in GM , which further confirmed the age‐related decline in mitochondrial content indicated by CS protein expression and enzymatic activity. The mRNA level of PGC‐1α, a master regulator of mitochondrial biogenesis, was lower in aged compared to young TB ( P <0.05). Consistently, the mRNA level of Tfam, which is involved in mitochondrial biogenesis and regulated by PGC‐1α, was decreased exclusively in aged TB ( P <0.05). Gene expression of the autophagy protein Microtubule‐Associated Protein Light Chain 3 (LC3) was higher in aged GM ( P <0.001) , but in either muscle age had no effect on gene expression of the autophagy‐associated Lysosomal Membrane Associated Protein‐2 (LAMP‐2), the transcription factor Nuclear Respiratory Factor‐1 (NRF‐1), and subunits of mitochondrial electron transport complexes ND1, COX1, and COX2. On a protein level, we observed an accumulation of the autophagosomal cargo protein SQSTM/p62 in both muscles ( P <0.05 for both), and, concomitantly, a decrease in the autophagy related protein Atg5 ( P <0.05) and the autophagosome‐bound form of LC3 (LC3‐II; P <0.05) in TB , suggesting impaired autophagosome formation in aged skeletal muscle. Taken together, our data suggest that mitochondrial biogenesis and autophagic activity were impacted by age in equine skeletal muscle, and that the TB is more susceptible to damage than the GM .
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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 | 0,000 | 0,000 |
| 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 ».