Mechanisms of cisplatin-induced muscle atrophy.
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 (3mg/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.
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan; Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan. Electronic address: sakai@hoshi.ac.jp.
Hiroyasu
H
Sakai
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Atsunobu
A
Sagara
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Kazuhiko
K
Arakawa
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Ryoto
R
Sugiyama
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Akiko
A
Hirosaki
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Kazuhide
K
Takase
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Ara
A
Jo
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan; Division of Pharmacy Professional Development and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Ken
K
Sato
Department of Biology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan.
Yoshihiko
Y
Chiba
Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 9300194, Japan.
Mitsuaki
M
Yamazaki
Department of Palliative Medicine and Psychooncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045, Japan.
Motohiro
M
Matoba
Department of Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 1428501, Japan. Electronic address: narita@hoshi.ac.jp.
Minoru
M
Narita
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology
D002945:Cisplatin
Cisplatin; Fatigue; Muscle RING finger-1; Muscle atrophy; Muscle atrophy F-box