Chin E R, Olson E N, Richardson J A, Yang Q, Humphries C, Shelton J M, Wu H, Zhu W, Bassel-Duby R, Williams R S
Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Genes Dev. 1998 Aug 15;12(16):2499-509. doi: 10.1101/gad.12.16.2499.
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.
成年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组合，这些独特的基因表达程序受运动神经元活动变化的控制。众所周知，由于神经刺激更为频繁，慢肌纤维比快肌纤维维持更高水平的细胞内游离钙，但钙作为将神经活动与骨骼肌基因表达变化联系起来的信使的作用机制尚不清楚。本文表明，骨骼肌中纤维类型特异性基因表达受一条信号通路控制，该通路涉及钙调神经磷酸酶，一种对环孢素敏感、受钙调节的丝氨酸/苏氨酸磷酸酶。骨骼肌细胞中钙调神经磷酸酶的激活选择性地上调慢肌纤维特异性基因启动子。相反，给完整动物施用环孢素A抑制钙调神经磷酸酶活性会促进慢肌纤维向快肌纤维的转变。慢肌纤维特异性转录的转录激活似乎由一种涉及NFAT和MEF2家族蛋白质的组合机制介导。这些结果确定了一种分子机制，通过该机制不同模式的运动神经活动促进基因表达的选择性变化，以建立慢肌纤维和快肌纤维的特殊特征。
