Departamento Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid 28871, Spain.
Unidad de Investigación de la Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid 28805, Spain.
Aging (Albany NY). 2020 Jun 22;12(12):11200-11223. doi: 10.18632/aging.103450.
Endothelial dysfunction, with increased endothelin-1 (ET-1) synthesis, and sarcopenia, characterized by the loss of muscular mass and strength, are two aging-related conditions. However, a relationship between them has not been already established. The aim of this study was to determine whether ET-1 induces senescence and fibrosis in cultured murine myoblasts, which could be involved in the development of sarcopenia related to aging. For this purpose, myoblasts were incubated with ET-1 to assess cellular senescence, analyzed by senescence associated β-galactosidase activity and p16 expression; and fibrosis, assessed by fibronectin expression. ET-1 induced myoblast senescence and fibrosis through ET receptor. The use of antioxidants and several antagonists revealed that ET-1 effect on senescence and fibrosis depended on ROS production and activation of PIK-AKT-GSK pathway. To stress the relevance of these results, circulating ET-1, muscular strength, muscular fibrosis and p16 expression were measured in male C57Bl6 mice from 5-18-24-months-old. Old mice shown high levels of ET-1 correlated with muscular fibrosis, muscular p16 expression and loss of muscle strength. In conclusion, ET-1 promotes fibrosis and senescence in cultured myoblasts, similar results were found in old mice, suggesting a potential role for ET-1 in the development of sarcopenia related to aging.
内皮功能障碍，伴随着内皮素-1（ET-1）合成增加，以及以肌肉质量和力量丧失为特征的肌肉减少症，是两种与衰老相关的情况。然而，它们之间的关系尚未确定。本研究的目的是确定 ET-1 是否会在培养的鼠肌肉成肌细胞中诱导衰老和纤维化，这可能与衰老相关的肌肉减少症的发展有关。为此，用 ET-1 孵育肌肉成肌细胞，以通过衰老相关β-半乳糖苷酶活性和 p16 表达来评估细胞衰老；通过纤连蛋白表达评估纤维化。ET-1 通过 ET 受体诱导肌肉成肌细胞衰老和纤维化。抗氧化剂和几种拮抗剂的使用表明，ET-1 对衰老和纤维化的影响取决于 ROS 的产生和 PIK-AKT-GSK 途径的激活。为了强调这些结果的相关性，在 5-18-24 个月大的雄性 C57Bl6 小鼠中测量了循环 ET-1、肌肉力量、肌肉纤维化和 p16 表达。老年小鼠表现出高水平的 ET-1，与肌肉纤维化、肌肉 p16 表达和肌肉力量丧失相关。总之，ET-1 可促进培养的肌肉成肌细胞中的纤维化和衰老，在老年小鼠中也发现了类似的结果，表明 ET-1 在与衰老相关的肌肉减少症的发展中具有潜在作用。
