Microtubule‐Targeting Chemotherapy Causes Mitochondrial Dysfunction in Heart and Skeletal Muscle
Notice bibliographique
Résumé
RATIONALE A variety of chemotherapies are associated with muscle dysfunction but the mechanisms are poorly understood. Emerging evidence suggests doxorubicin (DNA targeted chemotherapy) impairs mitochondrial respiration and increases H 2 O 2 emission. However, whether other chemotherapies create similar mitochondrial dysfunctions in muscle is unknown. An emerging model proposes that microtubules can inhibit mitochondrial ADP import/ATP export by blocking outer membrane voltage‐dependent anion channels (VDAC). We hypothesized that microtubule‐targeting chemotherapies (taxol, microtubule stabilizer; vinblastine, microtubule destabilizer) may alter ADP control of oxidative phosphorylation by changing VDAC‐permeability to ADP. We also hypothesized that these chemotherapies would alter mitochondrial H 2 O 2 emission considering ADP suppresses H 2 O 2 emission from mitochondria during oxidative phosphorylation. METHODS Mitochondrial ADP‐stimulated respiration and suppression of H 2 O 2 emission were assessed in permeabilized muscle fibres from skeletal muscle (soleus, extensor digitorum longus; EDL) and heart left ventricle following incubation with taxol and vinblastine for 2 and 1hr respectfully, at 4°C. RESULTS Diverse responses were observed with both microtubule stabilizing (taxol) and destabilizing (vinblastine) drugs. However, a consistent pattern emerged in heart whereby the stabilizer taxol decreased respiration (5mM ADP: control, 195.5 ± 33.6 pmol/s/mg w.w., taxol, 112.5 ± 19.6 pmols/s/mg w.w., p= 0.05) while the destabilizer vinblastine had no effect. Both stabilizer and destabilizer decreased the ability of ADP to suppress H 2 O 2 (taxol, 15 mM (p=0.03) and 100mM (p=0.02) ADP; vinblastine, 15mM to 500mM (p=0.01) ADP). No alterations were observed in succinate‐stimulated H 2 O 2 emission protocols, demonstrating that the responses in heart were surprisingly substrate‐specific. In EDL, ADP‐stimulated respiration was increased at submaximal [ADP] with destabilizer (250mM ADP: control, 15.29 ± 2.10, vinblastine, 22.75 ± 2.81 pmol/min/mg d.w., p=0.05) but did not change with stabilizer. Both drugs decreased ADP‐suppression of H 2 O 2 emission (with succinate) between 50mM to 500mM ADP (p=0.01). In soleus, ADP‐stimulated respiration and ADP‐suppression of H 2 O 2 did not change with either drug. CONCLUSIONS AND DISCUSSION Heart appears to be sensitive to microtubule‐targeted chemotherapy treatments as ADP‐stimulated respiration and suppression of H 2 O 2 were impaired. Oxidative soleus may be more resistant to alteration in microtubule structure as ADP‐stimulated respiration and suppression of H 2 O 2 did not change. In contrast, glycolytic EDL responded divergently to the destabilizer whereby ADP‐stimulated respiration was increased despite reduced ADP‐suppression of H 2 O 2 , whereas the stabilizer had no effect on respiration but also reduced ADP‐suppression of H 2 O 2. Collectively, microtubule‐stabilizing and destabilizing compounds inhibit ADP control of mitochondrial bioenergetics in heart and glycolytic skeletal muscle. Subsequent experiments will determine how these responses are related to microtubule‐VDAC binding and muscle functional capacities. Support or Funding Information Funding was provided to C.G.R.P. by National Science and Engineering Research Council (#436138‐2013) with infrastructure supported by Canada Foundation for Innovation, Ontario Research Fund and the James H. Cummings Foundation. S.V.R is supported by an OGS scholarship
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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 ».