| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Skeletal muscle is the largest organ in the human body and plays important roles in exercise, energy expenditure and glucose metabolism. Muscle atrophy is caused by being confined to bed, putting a broken leg or arm in a cast, starvation and diseases, including type I diabetes, and severely decreases the quality of life. However, the detailed molecular mechanisms on this process are not clearly understood. Previously, we showed that the gene expression of FOXO1, a forkhead transcription factor, was increased during atrophy, such as fasting, and the increased FOXO1 stimulated muscle atrophy.
In this study, we examined the gene expression events during muscle atrophy, in vivo and in vitro, especially focusing on FOXO1 and nuclear hormone receptors. We showed that FOXO1 enhanced expression of genes, which were involved in A) proteolysis, B) cell cycle inhibition and C) suppression of protein synthesis. Meanwhile, we showed that gene expression of RXR_γ was markedly decreased by fasting and
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was restored by refeeding in mouse skeletal muscle, in anti-parallel and parallel with changes in gene expression of FOXO1 and SREBP1c (a master regulator of lipogenesis), respectively. RXR_γ or RXRα, together with LXRα, activated the SREBP1c promoter in vitro. Moreover, transgenic mice overexpressing RXR_γ and those overexpressing its dominant negative form specifically in skeletal muscle showed increased and decreased gene expression of SREBP1c, respectively. The expression of FOXO1, which can suppress the function of multiple nuclear receptors, is negatively correlated to that of SREBP1c in skeletal muscle during nutritional change. Moreover, transgenic mice overexpressing FOXO1 specifically in skeletal muscle exhibited decreased gene expression of both RXR_γ and SREBP1c. In addition, FOXO1 suppressed RXRα/LXRα-mediated SREBP1c promoter activity in vitro. These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene expression, which is antagonized by FOXO1, in skeletal muscle. Less
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