New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Jeollanam-do, Republic of Korea.
PLoS One. 2021 May 26;16(5):e0252135. doi: 10.1371/journal.pone.0252135. eCollection 2021.
Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle.
骨骼肌萎缩是衰老（称为肌肉减少症）和各种疾病的特征，如癌症和肾衰竭。目前缺乏针对肌肉萎缩的有效药物治疗选择。正在评估绦虫药物氯硝柳胺是否可以重新用于治疗包括晚期癌症转移和肝脂肪变性在内的多种疾病。在这项研究中，我们研究了氯硝柳胺作为肌肉萎缩的再利用药物的潜力。在使用糖皮质激素地塞米松的肌管萎缩模型中，氯硝柳胺不能预防肌管直径的减小或磷酸化 FOXO3a 的表达降低，磷酸化 FOXO3a 上调肌肉分解代谢的泛素蛋白酶体途径。氯硝柳胺处理正常肌管不会激活肌肉蛋白合成的主要调节剂 mTOR，并增加在分解代谢状态下诱导的 atrogin-1 的表达。氯硝柳胺处理还抑制肌肉前体细胞的成肌作用，增加肌肉细胞标志物 Pax7 和 Myf5 的表达，并下调分化标志物 MyoD、MyoG 和 Myh2 的表达。在肌肉萎缩的动物模型中，氯硝柳胺不能改善肌肉质量、握力或肌纤维横截面积。肌肉萎缩也是癌症恶病质的特征。IC50 分析表明，氯硝柳胺对成肌细胞的细胞毒性比癌细胞更强。此外，氯硝柳胺在癌症恶病质的体外模型中不能抑制诱导型一氧化氮合酶（iNOS）的诱导，iNOS 是萎缩的关键介质，也不能挽救肌管直径。总的来说，这些结果表明氯硝柳胺可能不适合作为糖皮质激素诱导的骨骼肌萎缩或癌症恶病质的再利用药物。然而，氯硝柳胺可能被用作研究调节骨骼肌成肌作用和分解代谢途径的机制的化合物。
