Overexpression of FOXO1 in skeletal muscle does not alter longevity in mice
Overexpression of FOXO1 in skeletal muscle does not alter longevity in mice
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DOI：
10.1016/j.mad.2009.04.004
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发表时间：
2009-07-01
影响因子：
5.3
通讯作者：
Ezaki, Osamu
中科院分区：
文献类型：
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作者：
Chiba, Tsuyoshi;Kamei, Yasutomi;Ezaki, Osamu
热量限制（CR）是可以延长啮齿动物寿命的最强大和可重复的干预措施。对无脊椎动物的研究已经鉴定出了调节寿命的基因，其中一些基因编码胰岛素或胰岛素样信号通路的组分，包括β-16（C。elegans）和dFOXO（果蝇）。接受CR 8周的小鼠显示FOXO 1 mRNA和其他长寿相关基因的增加：骨骼肌中的Gadd 45 α、谷氨酰胺合成酶和过氧化氢酶。为了研究FOXO 1表达是否影响哺乳动物的寿命，研究了在骨骼肌中过表达FOXO 1的转基因小鼠（FOXO 1小鼠），其中发生肌肉萎缩。FOXO 1小鼠显示骨骼肌中Gadd 45 β和谷氨酰胺合酶蛋白的增加。在FOXO 1小鼠中，p70 S6 K和4 E-BP 1蛋白的磷酸化/去磷酸化状态没有改变，表明蛋白合成的翻译起始可能没有被抑制。FOXO 1小鼠的寿命与其野生型同窝仔相似。FOXO 1过表达不能阻止骨骼肌中过氧化氢酶、CuZu-SOD和Mn-SOD mRNA的衰老诱导的减少。这些数据表明，FOXO 1蛋白的增加及其在骨骼肌中的激活并不能延长小鼠的寿命。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Caloric restriction (CR) is the most robust and reproducible intervention that can extend lifespan in rodents. Studies in invertebrates have led to the identification of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signaling pathway, including DAF-16 (C. elegans) and dFOXO (Drosophila). Mice subjected to CR for 8 weeks showed an increase in FOXO1 mRNA and other longevity-related genes: Gadd 45 alpha, glutamine synthase, and catalase in skeletal muscle. To investigate whether FOXO1 expression affects longevity in mammals, transgenic mice were studied that overexpress FOXO1 in their skeletal muscle (FOXO1 mice), and in which muscle atrophy occurs. FOXO1 mice showed increases in Gadd 45(x, and glutamine synthase proteins in skeletal muscle. In FOXO1 mice, the phosphorylation/dephosphorylation state of the p70 S6K and 4E-BP1 proteins were not altered, suggesting that translation initiation of protein synthesis might not be suppressed. The lifespan of FOXO1 mice was similar to their wild-type littermates. FOXO1 overexpression could not prevent aging-induced reduction in catalase, CuZu-SOD, and Mn-SOD mRNA in skeletal muscle. These data suggest that an increase in FOXO1 protein and its activation in skeletal muscle does not extend lifespan in mice. (C) 2009 Elsevier Ireland Ltd. All rights reserved.