Chemotherapy Drugs Induce Cachexia and Alter Muscle Protein Metabolism
Notice bibliographique
Résumé
Chemotherapy is the main regimen to treat neoplastic tumours. Maintenance of muscle mass during treatment is associated with greater patient prognosis and reduces toxicity and severe side effects. However, chemotherapy induces cachexia, a wasting disorder characterized by muscle weakness and a loss of muscle mass. Although cancer, a disease treated with chemotherapy, is often diagnosed in older individuals, studies investigating chemotherapy‐induced cachexia are done exclusively in young animals at an age equivalent to a 20‐year‐old human. Therefore, studies investigating the effects of chemotherapy‐induced cachexia at an age range relevant to humans is needed. The objective of this study is to compare the severity and mechanisms of chemotherapy‐induced cachexia in 3‐month‐old adult (equivalent to a 20‐year‐old human) and 18‐month‐old (equivalent to a 56‐year‐old human) mice. Three‐month‐old adult CD2F1 male mice were treated with either folfiri (50mg/kg 5‐fluorouracil (5FU), 90mg/kg Leucovorin and 24mg/kg CPT11) (drug) or vehicle (10% DMSO in saline) for 6‐weeks. Male mice aged to 18‐months will undergo similar treatments. Adult mice treated with the drug cocktail exhibited significant body weight loss (~10%, n=4, p=0.0117) with no differences in food intake. Decreases in body weight were associated with a loss of muscle mass in the gastrocnemius (~25%, n=4, p=0.006), quadriceps (~30%, n=4, p=0.019) and tibialis anterior (~40%, n=4, p<0.0001). Insulin tolerance tests at weeks 3 and 6 of treatment were also performed and glucose levels were found to be non‐significantly higher in drug‐treated mice. Signalling factors related to the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), protein synthesis, autophagy and the ubiquitin proteasome system will be measured. Key enzymes responsible for the breakdown of the branched chain amino acids (BCAAs), mainly branched‐chain alpha‐ketoacid dehydrogenase complex (BCKD) and branched‐chain amino acid transferase 2 (BCAT2) will also be measured in the skeletal muscle. Along this line, in cell culture, we have previously shown decreased (~20%) activity of the BCKD enzyme, corresponding with decreased amino acid concentrations of leucine (~40%), isoleucine (~60%), valine (~50%), alanine (~30%), arginine (~60%), phenylalanine (50%), serine (50%) and glutamate (50%) in chemotherapy‐treated myotubes. We also observed decreased (~65%) expression of amino acid transporters sodium‐coupled neutral amino acid transporter 1 (SNAT1) and large neutral amino acid transporter 1 (LAT1). Timepoint analysis showed SNAT1 expression to be decreased prior to decreases in BCKD activity, signifying that alterations in BCAA metabolism may be a result of decreased levels of BCAAs and amino acids in chemotherapy‐treated myotubes. Therefore, these findings stemmed our interest in how the BCAAs, and their metabolites are affected in‐vivo following chemotherapy treatment. Findings from this study will help to elucidate whether unique signatures of cachexia are experienced in older mice. Better understanding of the mechanisms underlying muscle mass regulation following chemotherapy treatment may help combat cachexia.
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) | 0,000 | 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 ».