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A more recent version of this article appeared on April 1, 2006
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Submitted on August 19, 2005
Revised on January 6, 2006
Accepted on January 12, 2006
Departments of *Biochemistry and Molecular Biology and Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201
Monitoring Editor: Joseph Gall
The transcription factor NFATc1 may be involved in slow skeletal muscle gene expression. NFATc1 translocates from cytoplasm to nuclei during slow fiber type electrical stimulation of skeletal muscle fibers due to activation of the Ca2+ dependent phosphatase calcineurin, resulting in NFAT dephosphorylation and consequent exposure of its nuclear localization signal. Here we find that unstimulated adult skeletal muscle fibers exhibit a previously unanticipated nucleo-cytoplasmic shuttling of NFATc1 without appreciable nuclear accumulation. In resting fibers the nuclear export inhibitor leptomycin B caused nuclear accumulation of NFATc1 (but not of isoform NFATc3) and formation of NFATc1 intranuclear bodies independent of calcineurin. The rate of nuclear uptake of NFATc1 was 4.6 times lower in resting fibers exposed to leptomycin B than during electrical stimulation. Inhibitors of glycogen synthase kinase and protein kinase A or of casein kinase 1 slowed the decay of nuclear NFATc1 after electrical stimulation, but did not cause NFATc1 nuclear uptake in unstimulated fibers. We propose that two nuclear translocation pathways, one mediated by calcineurin activation and NFAT dephosphorylation and the other independent of calcineurin and possibly independent of NFAT dephosphorylation, determine the distribution of NFATc1 between cytoplasm and nuclei in adult skeletal muscle.
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