An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle.
An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle.
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DOI：
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发表时间：
2003
影响因子：
11.1
通讯作者：
C. Handschin;James Rhee;Jiandie D. Lin;Paul T. Tarr;B. Spiegelman
中科院分区：
文献类型：
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作者：
C. Handschin;James Rhee;Jiandie D. Lin;Paul T. Tarr;B. Spiegelman
骨骼肌通过诱导线粒体生物发生和将肌纤维比例从II型转换为I型来适应慢性体力活动。参与这一过程的几个主要因素已被确定，如钙/钙调蛋白依赖性蛋白激酶IV（CaMKIV），钙调神经磷酸酶A（CnA）和转录组分过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）。PGC-1 α的转基因表达可显著增加骨骼肌I型肌纤维的含量，但PGC-1 α表达与钙信号传导中的关键成分之间的关系尚不清楚。在这份报告中，我们表明，PGC-1 α启动子是由CaMKIV和CnA活性调节。CaMKIV主要通过cAMP反应元件结合蛋白与PGC-1 alpha启动子的结合来激活PGC-1 alpha。此外，我们发现PGC-1 α和肌细胞增强因子2（MEF 2）家族转录因子之间存在正反馈环。MEF 2与PGC-1 α启动子结合并激活它，主要是在被PGC-1 α共激活时。MEF 2活性进一步被CnA信号转导刺激。这些发现意味着一个统一的途径，整合钙信号与转录开关PGC-1 α的关键调节。此外，这些数据表明一个自动反馈回路，从而钙信号通路可能导致稳定的PGC-1 α诱导，有助于肌纤维类型确定的相对稳定的性质。
Skeletal muscle adapts to chronic physical activity by inducing mitochondrial biogenesis and switching proportions of muscle fibers from type II to type I. Several major factors involved in this process have been identified, such as the calcium/calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A (CnA), and the transcriptional component peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). Transgenic expression of PGC-1alpha recently has been shown to dramatically increase the content of type I muscle fibers in skeletal muscle, but the relationship between PGC-1alpha expression and the key components in calcium signaling is not clear. In this report, we show that the PGC-1alpha promoter is regulated by both CaMKIV and CnA activity. CaMKIV activates PGC-1alpha largely through the binding of cAMP response element-binding protein to the PGC-1alpha promoter. Moreover, we show that a positive feedback loop exists between PGC-1alpha and members of the myocyte enhancer factor 2 (MEF2) family of transcription factors. MEF2s bind to the PGC-1alpha promoter and activate it, predominantly when coactivated by PGC-1alpha. MEF2 activity is stimulated further by CnA signaling. These findings imply a unified pathway, integrating key regulators of calcium signaling with the transcriptional switch PGC-1alpha. Furthermore, these data suggest an autofeedback loop whereby the calcium-signaling pathway may result in a stable induction of PGC-1alpha, contributing to the relatively stable nature of muscle fiber-type determination.