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Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres

机译：转录共激活因子PGC-1α驱动慢肌纤维的形成

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The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type Ⅰ (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type Ⅱ (fast-twitch) fibres. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-γ co-activator-1 (PGC-1α), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism. We show here that PGC-1α is expressed preferentially in muscle enriched in type Ⅰ fibres. When PGC-1α is expressed at physiological levels in transgenic mice driven by a muscle creatine kinase (MCK) promoter, a fibre type conversion is observed: muscles normally rich in type Ⅱ fibres are redder and activate genes of mitochondrial oxidative metabolism. Notably, putative type Ⅱ muscles from PGC-1α transgenic mice also express proteins characteristic of type Ⅰ fibres, such as troponin Ⅰ (slow) and myoglobin, and show a much greater resistance to electrically stimulated fatigue. Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1α activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression. These data indicate that PGC-1α is a principal factor regulating muscle fibre type determination.
机译：骨骼肌中纤维类型测定的调节的生化基础尚不十分清楚。除了表达特定的肌原纤维蛋白外，Ⅰ型（慢肌）纤维的线粒体含量也更高，并且比Ⅱ型（快肌）纤维更依赖于氧化代谢。我们之前已经确定了转录共激活因子，过氧化物酶体增殖物激活的受体-γ共激活因子-1（PGC-1α），其在包括棕色脂肪和骨骼肌在内的多种组织中表达，并且可以激活线粒体的生物发生和氧化代谢。 。我们在这里表明，PGC-1α在富含Ⅰ型纤维的肌肉中优先表达。当PGC-1α在肌肉肌酸激酶（MCK）启动子驱动的转基因小鼠中以生理水平表达时，观察到纤维类型转换：通常富含Ⅱ型纤维的肌肉变红并激活线粒体氧化代谢基因。值得注意的是，PGC-1α转基因小鼠的推定的Ⅱ型肌肉还表达了Ⅰ型纤维的蛋白，例如肌钙蛋白Ⅰ（慢）和肌红蛋白，并且对电刺激的疲劳表现出更大的抵抗力。使用纤维类型特异性启动子，我们在培养的肌肉细胞中显示PGC-1α与Mef2蛋白协同激活转录，并充当钙调神经磷酸信号的靶标，而钙调磷酸酶信号传导与慢速纤维基因表达有关。这些数据表明PGC-1α是调节肌纤维类型确定的主要因素。

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