A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type
A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type
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DOI：
10.1101/gad.12.16.2499
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发表时间：
1998-08-15
影响因子：
10.5
通讯作者：
Williams, RS
中科院分区：
文献类型：
--
作者：
Chin, ER;Olson, EN;Williams, RS
成人骨骼肌的慢肌纤维和快肌纤维表达独特的肌肉特异性基因，这些独特的基因表达程序由运动神经元活动的变化控制。众所周知，由于更频繁的神经刺激，慢纤维比快纤维维持更高水平的细胞内游离钙，但钙作为连接骨骼肌中神经活动与基因表达变化的信使的机制尚不清楚。在这里，骨骼肌中纤维类型特异性基因表达被一个涉及钙调磷酸酶的信号通路所控制，钙调磷酸酶是一种环孢素敏感的、钙调节的丝氨酸/苏氨酸磷酸酶。骨骼肌细胞钙调磷酸酶的激活选择性上调慢纤维特异性基因启动子。相反，环孢素A对完整动物的钙调磷酸酶活性的抑制促进了纤维从慢到快的转化。慢纤维特异性转录的转录激活似乎是由涉及NFAT和MEF2家族蛋白的组合机制介导的。这些结果确定了一种分子机制，通过这种机制，运动神经活动的不同模式促进了基因表达的选择性变化，从而建立了慢速和快速肌纤维的特殊特征。
Slow- and fast-twitch myofibers of adult skeletal muscles express unique sets of muscle-specific genes, and these distinctive programs of gene expression are controlled by variations in motor neuron activity. It is well established that, as a consequence of more frequent neural stimulation, slow fibers maintain higher levels of intracellular free calcium than fast fibers, but the mechanisms by which calcium may function as a messenger linking nerve activity to changes in gene expression in skeletal muscle have been unknown. Here, fiber-type-specific gene expression in skeletal muscles is shown to be controlled by a signaling pathway that involves calcineurin, a cyclosporin-sensitive, calcium-regulated serine/threonine phosphatase. Activation of calcineurin in skeletal myocytes selectively up-regulates slow-fiber-specific gene promoters. Conversely, inhibition of calcineurin activity by administration of cyclosporin A to intact animals promotes slow-to-fast fiber transformation. Transcriptional activation of slow-fiber-specific transcription appears to be mediated by a combinatorial mechanism involving proteins of the NFAT and MEF2 families. These results identify a molecular mechanism by which different patterns of motor nerve activity promote selective changes in gene expression to establish the specialized characteristics of slow and fast myofibers.