Shen Tiansheng, Liu Yewei, Randall William R, Schneider Martin F
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201-1503, USA.
J Muscle Res Cell Motil. 2006;27(5-7):405-11. doi: 10.1007/s10974-006-9080-7. Epub 2006 Jul 28.
Skeletal muscle fibers exhibit plasticity of their physiological and biochemical properties in response to the firing pattern from the innervating motor neuron. In particular, the gene expression pattern generally characteristic of a slow twitch fiber can be induced in a fast twitch fiber by chronic slow fiber type electrical stimulation. We have studied the nucleo-cytoplasmic distribution of two transcriptional regulators of slow fiber type genes, HDAC4 and NFATc1, both in response to slow fiber type stimulation and in resting conditions using cultured fast twitch skeletal muscle fibers. HDAC4 is present in both cytoplasm and nuclei of resting fibers, and moves out of the nuclei in response to slow fiber type stimulation. The stimulation-dependent nuclear efflux of HDAC4 requires activation of nuclear CaMKII, which phosphorylates nuclear HDAC4 and thus allows its exit of the nucleus. In unstimulated resting fibers, a balance of nuclear efflux and influx of HDAC4 establishes the resting level of nuclear HDAC4. However, the nuclear efflux of HDAC4 in resting fibers does not involve CaMKII. Slow fiber type stimulation also causes NFATc1 translocation from the cytoplasm into muscle fiber nuclei following dephosphorylation by calcineurin (CaN) activated by the elevated cytosolic Ca2+ accompanying fiber stimulation. In resting fibers, NFATc1 exhibits balanced shuttling between cytoplasm and nucleus, but during this shuttling NFATc1 influx does not require CaN and NFATc1 efflux does not require the kinases involved in removing nuclear NFATc1 following prior activity. Thus different enzymes are responsible for HDAC4 nuclear efflux in resting and active fibers, and different pathways mediate NFATc1 nuclear influx and efflux in resting and active fibers. Such dual mechanisms for resting shuttling and active movements provide the potential for the resting level and the rate of translocation during fiber stimulation to be controlled independently for both of the transcriptional regulators HDAC4 and NFATc1.
骨骼肌纤维会根据支配运动神经元的放电模式，展现出生理和生化特性的可塑性。特别是，通过慢性慢肌纤维类型电刺激，快肌纤维中通常具有慢肌纤维特征的基因表达模式能够被诱导出来。我们利用培养的快肌骨骼肌纤维，研究了慢肌纤维类型基因的两种转录调节因子HDAC4和NFATc1在慢肌纤维类型刺激下以及静息状态时的核质分布。HDAC4存在于静息纤维的细胞质和细胞核中，并在慢肌纤维类型刺激下从细胞核中移出。HDAC4的刺激依赖性核外流需要核CaMKII的激活，核CaMKII使核HDAC4磷酸化，从而使其能够离开细胞核。在未受刺激的静息纤维中，HDAC4的核外流和内流平衡确立了核HDAC4的静息水平。然而，静息纤维中HDAC4的核外流并不涉及CaMKII。慢肌纤维类型刺激还会导致NFATc1在伴随着纤维刺激而升高的胞质Ca2+激活钙调神经磷酸酶（CaN）后去磷酸化，从而从细胞质转位到肌纤维细胞核中。在静息纤维中，NFATc1在细胞质和细胞核之间表现出平衡的穿梭，但在此穿梭过程中，NFATc1的内流不需要CaN，NFATc1的外流也不需要在先前活动后去除核内NFATc1所涉及的激酶。因此，不同的酶负责静息和活动纤维中HDAC4的核外流，不同的途径介导静息和活动纤维中NFATc1的核内流和外流。这种静息穿梭和活动转位的双重机制为HDAC4和NFATc1这两种转录调节因子在纤维刺激期间的静息水平和转位速率提供了独立控制的潜力。
