Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated type I (slow twitch/red muscle) fiber genes, and impaired glycemic control
Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated type I (slow twitch/red muscle) fiber genes, and impaired glycemic control
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DOI：
10.1074/jbc.m400674200
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发表时间：
2004-09-24
影响因子：
4.8
通讯作者：
Ezaki, O
中科院分区：
文献类型：
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作者：
Kamei, Y;Miura, S;Ezaki, O
FOXO 1是FOXO叉头型转录因子的成员，在能量剥夺状态如禁食和严重糖尿病时在骨骼肌中显著上调，但其在骨骼肌中的功能仍然知之甚少。在这项研究中，我们创建了骨骼肌特异性过表达FOXO 1的转基因小鼠。这些小鼠的体重低于野生型对照小鼠，骨骼肌质量减少，肌肉颜色更浅。微阵列分析显示，与I型肌肉（慢肌、红肌）结构蛋白相关的许多基因表达降低。组织学分析显示，FOXO 1小鼠骨骼肌中I型和II型纤维的尺寸显著减少，I型纤维的数量显著减少。已知在骨骼肌萎缩期间上调的溶酶体蛋白酶组织蛋白酶L的基因表达增强，表明FOXO 1小鼠骨骼肌中蛋白质降解增加。与对照小鼠相比，FOXO 1小鼠的转轮活动（自发运动活动）显著减少。此外，FOXO 1小鼠在口服葡萄糖和腹膜内胰岛素给药后显示血糖控制受损。这些结果表明，FOXO 1负调节骨骼肌质量和I型纤维基因表达，并导致骨骼肌功能受损。FOXO 1的激活可能参与肌肉减少症的发病机制，肌肉减少症是人类肌肉质量的年龄相关性下降，导致肥胖和糖尿病。
FOXO1, a member of the FOXO forkhead type transcription factors, is markedly up-regulated in skeletal muscle in energy-deprived states such as fasting and severe diabetes, but its functions in skeletal muscle have remained poorly understood. In this study, we created transgenic mice specifically overexpressing FOXO1 in skeletal muscle. These mice weighed less than the wildtype control mice, had a reduced skeletal muscle mass, and the muscle was paler in color. Microarray analysis revealed that the expression of many genes related to the structural proteins of type I muscles (slow twitch, red muscle) was decreased. Histological analyses showed a marked decrease in size of both type I and type II fibers and a significant decrease in the number of type I fibers in the skeletal muscle of FOXO1 mice. Enhanced gene expression of a lysosomal proteinase, cathepsin L, which is known to be up-regulated during skeletal muscle atrophy, suggested increased protein degradation in the skeletal muscle of FOXO1 mice. Running wheel activity (spontaneous locomotive activity) was significantly reduced in FOXO1 mice compared with control mice. Moreover, the FOXO1 mice showed impaired glycemic control after oral glucose and intraperitoneal insulin administration. These results suggest that FOXO1 negatively regulates skeletal muscle mass and type I fiber gene expression and leads to impaired skeletal muscle function. Activation of FOXO1 may be involved in the pathogenesis of sarcopenia, the age-related decline in muscle mass in humans, which leads to obesity and diabetes.