Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia
Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia
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DOI：
10.18632/aging.103450
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发表时间：
2020-06-30
期刊：
影响因子：
5.2
通讯作者：
Lopez-Ongil, Susana
中科院分区：
文献类型：
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作者：
Alcalde-Estevez, Elena;Asenjo-Bueno, Ana;Lopez-Ongil, Susana
内皮功能障碍，增加内皮素-1（ET-1）的合成，和肌肉减少症，其特征在于肌肉质量和力量的损失，是两个与衰老有关的条件。然而，它们之间的关系尚未建立。本研究的目的是确定ET-1是否诱导培养的小鼠成肌细胞的衰老和纤维化，这可能涉及与衰老相关的肌肉减少症的发展。为此，将成肌细胞与ET-1孵育以评估细胞衰老，通过衰老相关的β-半乳糖苷酶活性和p16表达进行分析;并通过纤连蛋白表达评估纤维化。ET-1通过ETA受体诱导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对衰老和纤维化的作用依赖于ROS的产生和PI 3 K-AKT-GSK通路的激活。为了强调这些结果的体内相关性，在5-18-24月龄的雄性C57 B16小鼠中测量循环ET-1、肌肉强度、肌肉纤维化和p16表达。老年小鼠显示高水平的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促进成肌细胞的纤维化和衰老，在老年小鼠中发现了类似的结果，表明ET-1在与衰老相关的肌肉减少症的发展中的潜在作用。
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 beta-galactosidase activity and p16 expression; and fibrosis, assessed by fibronectin expression. ET-1 induced myoblast senescence and fibrosis through ETA receptor. The use of antioxidants and several antagonists revealed that ET-1 effect on senescence and fibrosis depended on ROS production and activation of PI3K-AKT-GSK pathway. To stress the in vivo 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.