論文 - 詳細
| RRC ID | 68869 |
|---|---|
| 著者 | Sakai H, Asami M, Naito H, Kitora S, Suzuki Y, Miyauchi Y, Tachinooka R, Yoshida S, Kon R, Ikarashi N, Chiba Y, Kamei J. |
| タイトル | Exogenous insulin-like growth factor 1 attenuates cisplatin-induced muscle atrophy in mice. |
| ジャーナル | J Cachexia Sarcopenia Muscle |
| Abstract |
BACKGROUND:A reduction in the skeletal muscle mass worsens the prognosis of patients with various cancers. Our previous studies indicated that cisplatin administration to mice caused muscle atrophy. This is a concern for human patients receiving cisplatin. The insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway stimulates the rate of protein synthesis in skeletal muscle. Thus, IGF-I can be a central therapeutic target for preventing the loss of skeletal muscle mass in muscle atrophy, although it remains unclear whether pharmacological activation of the IGF-1/PI3K/Akt pathway attenuates muscle atrophy induced by cisplatin. In this study, we examined whether exogenous recombinant human IGF-1 attenuated cisplatin-induced muscle atrophy. METHODS:Male C57BL/6J mice (8-9 weeks old) were injected with cisplatin or saline for four consecutive days. On Day 5, quadriceps muscles were isolated. Mecasermin (recombinant human IGF-1) or the vehicle control was subcutaneously administered 30 min prior to cisplatin administration. A dietary restriction group achieving weight loss equivalent to that caused by cisplatin administration was used as a second control. C2C12 myotubes were treated with cisplatin with/without recombinant mouse IGF-1. The skeletal muscle protein synthesis/degradation pathway was analysed by histological and biochemical methods. RESULTS:Cisplatin reduced protein level of IGF-1 by about 85% compared with the vehicle group and also reduced IGF-1/PI3K/Akt signalling in skeletal muscle. Under this condition, the protein levels of muscle ring finger protein 1 (MuRF1) and atrophy gene 1 (atrogin-1) were increased in quadriceps muscles (MuRF1; 3.0 ± 0.1 folds, atrogin-1; 3.0 ± 0.3 folds, P < 0.001, respectively). The administration of a combination of cisplatin and IGF-1 significantly suppressed the cisplatin-induced downregulation of IGF-1/PI3K/Akt signalling and upregulation of MuRF1 and atrogin-1 (up to 1.6 ± 0.3 and 1.5 ± 0.4 folds, P < 0.001, respectively), resulting in diminished muscular atrophy. IGF-1 showed similar effects in cisplatin-treated C2C12 myotubes, as well as the quadriceps muscle in mice. CONCLUSIONS:The downregulation of IGF-1 expression in skeletal muscle might be one of the factors playing an important role in the development of cisplatin-induced muscular atrophy. Compensating for this downregulation with exogenous IGF-1 suggests that it could be a therapeutic target for limiting the loss of skeletal muscle mass in cisplatin-induced muscle atrophy. |
| 巻・号 | 12(6) |
| ページ | 1570-1581 |
| 公開日 | 2021-12-1 |
| DOI | 10.1002/jcsm.12760 |
| PMID | 34268902 |
| PMC | PMC8718074 |
| MeSH | Animals Cisplatin / adverse effects Humans Insulin-Like Growth Factor I* Male Mice Mice, Inbred C57BL Muscle Proteins / genetics Muscular Atrophy / chemically induced Muscular Atrophy / drug therapy Phosphatidylinositol 3-Kinases* Ubiquitin-Protein Ligases |
| IF | 12.511 |
| リソース情報 | |
| ヒト・動物細胞 | C2C12(RCB0987) |