Department of Biomolecular Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Department of Physiology and Molecular Sciences, School of Pharmacy, Hoshi University, Tokyo, Japan.
J Cachexia Sarcopenia Muscle. 2021 Dec;12(6):1570-1581. doi: 10.1002/jcsm.12760. Epub 2021 Jul 16.
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.
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.
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.
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.
骨骼肌质量的减少会使各种癌症患者的预后恶化。我们之前的研究表明，顺铂给药会导致小鼠肌肉萎缩。这是接受顺铂治疗的人类患者所关心的问题。胰岛素样生长因子 1（IGF-1）/磷酸肌醇 3-激酶（PI3K）/Akt 途径刺激骨骼肌中蛋白质的合成速率。因此，IGF-I 可以成为预防肌肉萎缩引起的骨骼肌质量损失的中心治疗靶点，尽管尚不清楚药理学激活 IGF-1/PI3K/Akt 途径是否能减轻顺铂引起的肌肉萎缩。在这项研究中，我们研究了外源性重组人 IGF-1 是否能减轻顺铂引起的肌肉萎缩。
雄性 C57BL/6J 小鼠（8-9 周龄）连续 4 天接受顺铂或生理盐水注射。第 5 天，分离股四头肌。Mecasermin（重组人 IGF-1）或载体对照在给予顺铂前 30 分钟皮下给药。体重减轻相当于顺铂给药引起的体重减轻的饮食限制组被用作第二个对照。C2C12 肌管用顺铂处理，有/无重组鼠 IGF-1。通过组织学和生化方法分析骨骼肌蛋白质合成/降解途径。
与载体组相比，顺铂使 IGF-1 的蛋白水平降低了约 85%，并且还降低了骨骼肌中的 IGF-1/PI3K/Akt 信号。在这种情况下，股四头肌中肌肉环指蛋白 1（MuRF1）和萎缩基因 1（atrogin-1）的蛋白水平增加（MuRF1；3.0±0.1 倍，atrogin-1；3.0±0.3 倍，P<0.001）。顺铂和 IGF-1 的联合给药显著抑制了顺铂诱导的 IGF-1/PI3K/Akt 信号下调和 MuRF1 和 atrogin-1 的上调（分别高达 1.6±0.3 和 1.5±0.4 倍，P<0.001），从而减轻了肌肉萎缩。IGF-1 对顺铂处理的 C2C12 肌管以及小鼠的股四头肌也有类似的作用。
骨骼肌中 IGF-1 表达的下调可能是顺铂诱导肌肉萎缩发展的重要因素之一。用外源性 IGF-1 来补偿这种下调表明，它可能是限制顺铂诱导肌肉萎缩中骨骼肌质量损失的治疗靶点。
