Liu Yewei, Randall William R, Schneider Martin F
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Cell Biol. 2005 Mar 14;168(6):887-97. doi: 10.1083/jcb.200408128.
Class II histone deacetylases (HDACs) may decrease slow muscle fiber gene expression by repressing myogenic transcription factor myocyte enhancer factor 2 (MEF2). Here, we show that repetitive slow fiber type electrical stimulation, but not fast fiber type stimulation, caused HDAC4-GFP, but not HDAC5-GFP, to translocate from the nucleus to the cytoplasm in cultured adult skeletal muscle fibers. HDAC4-GFP translocation was blocked by calmodulin-dependent protein kinase (CaMK) inhibitor KN-62. Slow fiber type stimulation increased MEF2 transcriptional activity, nuclear Ca(2+) concentration, and nuclear levels of activated CaMKII, but not total nuclear CaMKII or CaM-YFP. Thus, calcium transients for slow, but not fast, fiber stimulation patterns appear to provide sufficient Ca(2+)-dependent activation of nuclear CaMKII to result in net nuclear efflux of HDAC4. Nucleocytoplasmic shuttling of HDAC4-GFP in unstimulated resting fibers was not altered by KN-62, but was blocked by staurosporine, indicating that different kinases underlie nuclear efflux of HDAC4 in resting and stimulated muscle fibers.
II类组蛋白去乙酰化酶（HDACs）可能通过抑制肌源性转录因子肌细胞增强因子2（MEF2）来降低慢肌纤维基因的表达。在此，我们发现重复性慢纤维类型电刺激而非快纤维类型刺激，可导致培养的成年骨骼肌纤维中HDAC4 - GFP从细胞核转位至细胞质，但HDAC5 - GFP无此现象。HDAC4 - GFP转位被钙调蛋白依赖性蛋白激酶（CaMK）抑制剂KN - 62阻断。慢纤维类型刺激增加了MEF2转录活性、核Ca(2+)浓度以及活化的CaMKII的核水平，但未增加总核CaMKII或CaM - YFP的水平。因此，慢纤维而非快纤维刺激模式的钙瞬变似乎能提供足够的依赖Ca(2+)的核CaMKII激活，从而导致HDAC4的净核外流。在未受刺激的静息纤维中，KN - 62并未改变HDAC4 - GFP的核质穿梭，但星形孢菌素可阻断其穿梭，这表明在静息和受刺激的肌纤维中，HDAC4的核外流由不同的激酶介导。
