MuRF1 Deficiency Prevents Age‐Related Fat Weight Gain, Possibly Through Accumulation of PDK4 in Skeletal Muscle Mitochondria in Older Mice
MuRF1 Deficiency Prevents Age‐Related Fat Weight Gain, Possibly Through Accumulation of PDK4 in Skeletal Muscle Mitochondria in Older Mice
复制标题
MuRF1 缺乏可防止与年龄相关的脂肪体重增加，可能是通过老年小鼠骨骼肌线粒体中 PDK4 的积累
DOI：
10.1002/jor.25131
复制
发表时间：
2021
影响因子：
2.8
通讯作者：
Nikawa Takeshi
中科院分区：
文献类型：
--
作者：
Sugiura Kosuke;Hirasaka Katsuya;Maeda Tasuku;Uchida Takayuki;Kishimoto Koji;Oarada Motoko;Labeit Siegfried;Ulla Anayt;Sakakibara Iori;Nakao Reiko;Sairyo Koichi;Nikawa Takeshi
最近的研究表明，肌肉质量和代谢功能是相互联系的。肌环指1 （MuRF1）是一种与肌肉萎缩相关的关键肌肉特异性泛素连接酶。然而，MuRF1在萎缩和衰老中的分子靶点尚不清楚。我们使用体内缺乏MuRF1 （MuRF1 - / -）的小鼠和体外过表达MuRF1的细胞，研究了MuRF1在衰老中的作用。MuRF1缺乏部分阻止小鼠年龄诱导的骨骼肌损失。有趣的是，超过7个月大的MuRF1 - / -小鼠的体重和脂肪量低于MuRF1+/+小鼠。血清和肌肉代谢参数以及间接量热法结果表明，3个月大的MuRF1 - / -小鼠的能量消耗和脂质代谢明显高于MuRF1+/+小鼠，从而抑制了衰老过程中脂肪组织的增加。丙酮酸脱氢酶激酶4 （PDK4）是葡萄糖代谢向脂质代谢转换的关键，我们研究了MuRF1和PDK4之间的相互作用。MuRF1 - / -小鼠骨骼肌线粒体中PDK4蛋白水平升高。在体外，MuRF1与PDK4相互作用，但不通过泛素化诱导降解。相反，与没有MuRF1环结构域的细胞相比，在MuRF1过表达的细胞中检测到PDK4的SUMO转录后修饰（SUMOylation）。MuRF1缺乏可能通过阻止SUMOylation而上调PDK4在线粒体中的定位，从而增强脂质代谢。抑制MuRF1介导的PDK4 summoylation是治疗与年龄相关的脂质代谢功能障碍和肌肉萎缩的潜在治疗靶点。
Recent studies show that muscle mass and metabolic function are interlinked. Muscle RING finger 1 (MuRF1) is a critical muscle‐specific ubiquitin ligase associated with muscle atrophy. Yet, the molecular target of MuRF1 in atrophy and aging remains unclear. We examined the role of MuRF1 in aging, using MuRF1‐deficient (MuRF1–/–) mice in vivo, and MuRF1‐overexpressing cell in vitro. MuRF1 deficiency partially prevents age‐induced skeletal muscle loss in mice. Interestingly, body weight and fat mass of more than 7‐month‐old MuRF1–/–mice were lower than in MuRF1+/+mice. Serum and muscle metabolic parameters and results of indirect calorimetry suggest significantly higher energy expenditure and enhanced lipid metabolism in 3‐month‐old MuRF1–/–mice than in MuRF1+/+mice, resulting in suppressed adipose tissue gain during aging. Pyruvate dehydrogenase kinase 4 (PDK4) is crucial for a switch from glucose to lipid metabolism, and the interaction between MuRF1 and PDK4 was examined. PDK4 protein levels were elevated in mitochondria from the skeletal muscle in MuRF1–/–mice. In vitro, MuRF1 interacted with PDK4 but did not induce degradation through ubiquitination. Instead, SUMO posttranscriptional modification (SUMOylation) of PDK4 was detected in MuRF1‐overexpressing cells, in contrast to cells without the RING domain of MuRF1. MuRF1 deficiency enhances lipid metabolism possibly by upregulating PDK4 localization into mitochondrial through prevention of SUMOylation. Inhibition of MuRF1‐mediated PDK4 SUMOylation is a potential therapeutic target for age‐related dysfunction of lipid metabolism and muscle atrophy.