NFAT isoforms control activity-dependent muscle fiber type specification
NFAT isoforms control activity-dependent muscle fiber type specification
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DOI：
10.1073/pnas.0812911106
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发表时间：
2009-08-11
影响因子：
11.1
通讯作者：
Murgia, Marta
中科院分区：
文献类型：
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作者：
Calabria, Elisa;Ciciliot, Stefano;Murgia, Marta
将快速和慢速运动神经元活动转化为肌纤维类型特异性转录程序的细胞内信号仅得到部分定义。钙/钙调蛋白依赖性磷酸酶钙调神经磷酸酶 (Cn) 已被证明可以介导运动神经元活动的转录效应，但 4 种不同的肌纤维类型到底是如何组成和维持以响应活动的，在很大程度上尚不清楚。在这里，我们发现激活 T 细胞 (NFAT) 家族成员的 4 个核因子在肌纤维类型的规范中协调作用于 Cn 下游。我们通过 RNAi 功能丧失方法瞬时转染骨骼肌，分析了 NFAT 家族成员在体内的作用。我们的结果表明，根据所应用的活动模式，NFAT 家族成员的不同组合易位到细胞核，有助于纤维类型特定基因的转录。我们提供的证据表明，慢肌球蛋白重链和快肌球蛋白重链 (MyHC) 基因的转录使用 NFAT 家族成员的不同组合，从使用所有 4 种 NFAT 亚型的 MyHC-slow 到仅使用 NFATc4 的 MyHC-2B。我们的数据有助于阐明活动调节骨骼肌表型和性能的机制。
The intracellular signals that convert fast and slow motor neuron activity into muscle fiber type specific transcriptional programs have only been partially defined. The calcium/calmodulin-dependent phosphatase calcineurin (Cn) has been shown to mediate the transcriptional effects of motor neuron activity, but precisely how 4 distinct muscle fiber types are composed and maintained in response to activity is largely unknown. Here, we show that 4 nuclear factor of activated T cell (NFAT) family members act coordinately downstream of Cn in the specification of muscle fiber types. We analyzed the role of NFAT family members in vivo by transient transfection in skeletal muscle using a loss-of-function approach by RNAi. Our results show that, depending on the applied activity pattern, different combinations of NFAT family members translocate to the nucleus contributing to the transcription of fiber type specific genes. We provide evidence that the transcription of slow and fast myosin heavy chain (MyHC) genes uses different combinations of NFAT family members, ranging from MyHC-slow, which uses all 4 NFAT isoforms, to MyHC-2B, which only uses NFATc4. Our data contribute to the elucidation of the mechanisms whereby activity can modulate the phenotype and performance of skeletal muscle.