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Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle.

Liu Y, Randall WR, Schneider MF - J. Cell Biol. (2005)

Bottom Line: Class II histone deacetylases (HDACs) may decrease slow muscle fiber gene expression by repressing myogenic transcription factor myocyte enhancer factor 2 (MEF2).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

ABSTRACT
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.

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Time course of nuclear to cytoplasmic translocation of HDAC4 with 1- or 100-Hz stimulation. (A) 1-Hz continuous stimulation resulted in nuclear to cytoplasmic translocation of HDAC4-GFP, but with a lower mean initial net export rates compared with 10-Hz trains. The 10-Hz trains were more effective than 1 Hz in causing HDAC4-GFP nuclear export. Nuclear fluorescence declined continuously during the 120-min stimulation period. The cytoplasmic fluorescence remained constant during the same period of time. (B) 100-ms train at 100 Hz every 50 s did not have effects on the subcellular distribution of HDAC4-GFP.
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fig4: Time course of nuclear to cytoplasmic translocation of HDAC4 with 1- or 100-Hz stimulation. (A) 1-Hz continuous stimulation resulted in nuclear to cytoplasmic translocation of HDAC4-GFP, but with a lower mean initial net export rates compared with 10-Hz trains. The 10-Hz trains were more effective than 1 Hz in causing HDAC4-GFP nuclear export. Nuclear fluorescence declined continuously during the 120-min stimulation period. The cytoplasmic fluorescence remained constant during the same period of time. (B) 100-ms train at 100 Hz every 50 s did not have effects on the subcellular distribution of HDAC4-GFP.

Mentions: 1-Hz continuous stimulation also caused the exit of HDAC4-GFP from the nucleus (Fig. 4 A), but the efflux was somewhat lower than with the 10-Hz trains. Using linear fits to the data from each fiber, the mean initial net export rate during the first 30 min of 1-Hz continuous stimulation was −0.45 ± 0.10%/min over (10 nuclei from 5 fibers), which is slower than the corresponding value of −0.62 ± 0.12%/min obtained from the fibers stimulated with 5-s 10-Hz trains every 50 s (Fig. 2 A; 10 nuclei from 6 fibers). In contrast to the 10-Hz train stimulation (Fig. 2 A), which is typical for slow type fibers, using 100-ms trains at 100 Hz every 50 s, which is a typical pattern of fast fiber type activity (Hennig and Lomo, 1985), did not cause any detectable change in nuclear fluorescence, indicating negligible net nucleus to cytoplasm translocation of HDAC4-GFP with the fast fiber type stimulation pattern (Fig. 4 B, eight nuclei from six fibers). Thus, we conclude that the rate and extent of loss of nuclear HDAC4 is determined by the pattern of activity experienced by the muscle fibers, and that the typical slow pattern of stimulation, but not the fast pattern, induces nuclear to cytoplasmic translocation of HDAC4.


Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle.

Liu Y, Randall WR, Schneider MF - J. Cell Biol. (2005)

Time course of nuclear to cytoplasmic translocation of HDAC4 with 1- or 100-Hz stimulation. (A) 1-Hz continuous stimulation resulted in nuclear to cytoplasmic translocation of HDAC4-GFP, but with a lower mean initial net export rates compared with 10-Hz trains. The 10-Hz trains were more effective than 1 Hz in causing HDAC4-GFP nuclear export. Nuclear fluorescence declined continuously during the 120-min stimulation period. The cytoplasmic fluorescence remained constant during the same period of time. (B) 100-ms train at 100 Hz every 50 s did not have effects on the subcellular distribution of HDAC4-GFP.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171787&req=5

fig4: Time course of nuclear to cytoplasmic translocation of HDAC4 with 1- or 100-Hz stimulation. (A) 1-Hz continuous stimulation resulted in nuclear to cytoplasmic translocation of HDAC4-GFP, but with a lower mean initial net export rates compared with 10-Hz trains. The 10-Hz trains were more effective than 1 Hz in causing HDAC4-GFP nuclear export. Nuclear fluorescence declined continuously during the 120-min stimulation period. The cytoplasmic fluorescence remained constant during the same period of time. (B) 100-ms train at 100 Hz every 50 s did not have effects on the subcellular distribution of HDAC4-GFP.
Mentions: 1-Hz continuous stimulation also caused the exit of HDAC4-GFP from the nucleus (Fig. 4 A), but the efflux was somewhat lower than with the 10-Hz trains. Using linear fits to the data from each fiber, the mean initial net export rate during the first 30 min of 1-Hz continuous stimulation was −0.45 ± 0.10%/min over (10 nuclei from 5 fibers), which is slower than the corresponding value of −0.62 ± 0.12%/min obtained from the fibers stimulated with 5-s 10-Hz trains every 50 s (Fig. 2 A; 10 nuclei from 6 fibers). In contrast to the 10-Hz train stimulation (Fig. 2 A), which is typical for slow type fibers, using 100-ms trains at 100 Hz every 50 s, which is a typical pattern of fast fiber type activity (Hennig and Lomo, 1985), did not cause any detectable change in nuclear fluorescence, indicating negligible net nucleus to cytoplasm translocation of HDAC4-GFP with the fast fiber type stimulation pattern (Fig. 4 B, eight nuclei from six fibers). Thus, we conclude that the rate and extent of loss of nuclear HDAC4 is determined by the pattern of activity experienced by the muscle fibers, and that the typical slow pattern of stimulation, but not the fast pattern, induces nuclear to cytoplasmic translocation of HDAC4.

Bottom Line: Class II histone deacetylases (HDACs) may decrease slow muscle fiber gene expression by repressing myogenic transcription factor myocyte enhancer factor 2 (MEF2).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus