Calabria Elisa, Ciciliot Stefano, Moretti Irene, Garcia Marta, Picard Anne, Dyar Kenneth A, Pallafacchina Giorgia, Tothova Jana, Schiaffino Stefano, Murgia Marta
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13335-40. doi: 10.1073/pnas.0812911106. Epub 2009 Jul 24.
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.
将快速和慢速运动神经元活动转化为肌肉纤维类型特异性转录程序的细胞内信号仅得到了部分定义。钙/钙调蛋白依赖性磷酸酶钙调神经磷酸酶（Cn）已被证明可介导运动神经元活动的转录效应，但对于4种不同的肌肉纤维类型如何响应活动而组成和维持，很大程度上仍不清楚。在这里，我们表明4种活化T细胞核因子（NFAT）家族成员在肌肉纤维类型的特异性分化中在Cn的下游协同作用。我们通过RNA干扰的功能丧失方法，在骨骼肌中进行瞬时转染，分析了NFAT家族成员在体内的作用。我们的结果表明，根据所施加的活动模式，NFAT家族成员的不同组合会转运到细胞核，促进纤维类型特异性基因的转录。我们提供的证据表明，慢速和快速肌球蛋白重链（MyHC）基因的转录使用了不同的NFAT家族成员组合，从使用所有4种NFAT异构体的MyHC-慢型，到仅使用NFATc4的MyHC-2B型。我们的数据有助于阐明活动能够调节骨骼肌表型和性能的机制。
