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Title: Mechanisms of cisplatin-induced muscle atrophy

Abstract

Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggestmore » that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.« less

Authors:
 [1];  [2]; ; ; ; ; ;  [1];  [1];  [2];  [3];  [4];  [5];  [1]
  1. Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)
  2. (Japan)
  3. Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 (Japan)
  4. Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194 (Japan)
  5. Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045 (Japan)
Publication Date:
OSTI Identifier:
22439790
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 278; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATROPHY; CHEMOTHERAPY; COMPARATIVE EVALUATIONS; DRUGS; FATIGUE; FINGERS; FOOD; GENES; INTAKE; LOSSES; MESSENGER-RNA; MICE; MUSCLES; NEOPLASMS; PHOSPHORYLATION; PLATINUM; PROTEINS; WEIGHT

Citation Formats

Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp, Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Sagara, Atsunobu, Arakawa, Kazuhiko, Sugiyama, Ryoto, Hirosaki, Akiko, Takase, Kazuhide, Jo, Ara, Sato, Ken, Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Chiba, Yoshihiko, Yamazaki, Mitsuaki, Matoba, Motohiro, and Narita, Minoru, E-mail: narita@hoshi.ac.jp. Mechanisms of cisplatin-induced muscle atrophy. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.05.001.
Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp, Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Sagara, Atsunobu, Arakawa, Kazuhiko, Sugiyama, Ryoto, Hirosaki, Akiko, Takase, Kazuhide, Jo, Ara, Sato, Ken, Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Chiba, Yoshihiko, Yamazaki, Mitsuaki, Matoba, Motohiro, & Narita, Minoru, E-mail: narita@hoshi.ac.jp. Mechanisms of cisplatin-induced muscle atrophy. United States. doi:10.1016/J.TAAP.2014.05.001.
Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp, Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Sagara, Atsunobu, Arakawa, Kazuhiko, Sugiyama, Ryoto, Hirosaki, Akiko, Takase, Kazuhide, Jo, Ara, Sato, Ken, Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Chiba, Yoshihiko, Yamazaki, Mitsuaki, Matoba, Motohiro, and Narita, Minoru, E-mail: narita@hoshi.ac.jp. 2014. "Mechanisms of cisplatin-induced muscle atrophy". United States. doi:10.1016/J.TAAP.2014.05.001.
@article{osti_22439790,
title = {Mechanisms of cisplatin-induced muscle atrophy},
author = {Sakai, Hiroyasu, E-mail: sakai@hoshi.ac.jp and Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 and Sagara, Atsunobu and Arakawa, Kazuhiko and Sugiyama, Ryoto and Hirosaki, Akiko and Takase, Kazuhide and Jo, Ara and Sato, Ken and Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501 and Chiba, Yoshihiko and Yamazaki, Mitsuaki and Matoba, Motohiro and Narita, Minoru, E-mail: narita@hoshi.ac.jp},
abstractNote = {Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.},
doi = {10.1016/J.TAAP.2014.05.001},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 278,
place = {United States},
year = 2014,
month = 7
}
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