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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription
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PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription

机译：PGC-1α通过抑制FoxO3作用和萎缩特异性基因转录来保护骨骼肌免于萎缩

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摘要

Maintaining muscle size and fiber composition requires contractile activity. Increased activity stimulates expression of the transcrip-tional coactivator PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which promotes fiber-type switching from glycolytic toward more oxidative fibers. In response to disuse or denervation, but also in fasting and many systemic diseases, muscles undergo marked atrophy through a common set of tran-scriptional changes. FoxO family transcription factors play a critical role in this loss of cell protein, and when activated, FoxO3 causes expression of the atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 and profound loss of muscle mass. To understand how exercise might retard muscle atrophy, we investigated the possible interplay between PGC-1α and the FoxO family in regulation of muscle size. Rodent muscles showed a large decrease in PGC-1α mRNA during atrophy induced by denervation as well as by cancer cachexia, diabetes, and renal failure. Furthermore, in transgenic mice overexpressing PGC-1α, denervation and fasting caused a much smaller decrease in muscle fiber diameter and a smaller induction of atrogin-1 and MuRF-1 than in control mice. Increased expression of PGC-1α also increased mRNA for several genes involved in energy metabolism whose expression decreases during atrophy. Transfection of PGC-1α into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter. Thus, the high levels of PGC-1α in dark and exercising muscles can explain their resistance to atrophy, and the rapid fall in PGC-1α during atrophy should enhance the FoxO-dependent loss of muscle mass.
机译：保持肌肉大小和纤维成分需要收缩活动。活性增加会刺激转录共激活因子PGC-1α（过氧化物酶体增殖物激活的受体γ共激活因子1α）的表达，从而促进纤维类型从糖酵解型向氧化性更高的纤维转变。为了响应停用或神经支配，以及在禁食和许多全身性疾病中，肌肉会通过一组常见的转录变化而经历明显的萎缩。 FoxO家族转录因子在这种细胞蛋白的丧失中起关键作用，当被激活时，FoxO3导致与萎缩相关的泛素连接酶atrogin-1和MuRF-1的表达以及肌肉质量的严重丧失。为了了解运动如何阻碍肌肉萎缩，我们调查了PGC-1α和FoxO家族在调节肌肉大小方面可能的相互作用。啮齿动物的肌肉在神经支配以及癌症恶病质，糖尿病和肾功能衰竭引起的萎缩过程中，PGC-1αmRNA大量下降。此外，在过表达PGC-1α的转基因小鼠中，与对照小鼠相比，去神经支配和禁食导致肌肉纤维直径的减小小得多，对atrogin-1和MuRF-1的诱导也小得多。 PGC-1α表达的增加也增加了能量代谢中涉及的几个基因的mRNA表达，这些基因在萎缩过程中表达下降。将PGC-1α转染到成年纤维中会降低FoxO3引起纤维萎缩并与atrogin-1启动子结合并转录的能力。因此，在黑暗和运动中的肌肉中高水平的PGC-1α可以解释其对萎缩的抵抗力，并且在萎缩过程中PGC-1α的快速下降应增强FoxO依赖性的肌肉质量损失。

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