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Vol. 17, Issue 4, 1570-1582, April 2006

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Activity- and Calcineurin-independent Nuclear Shuttling of NFATc1, but Not NFATc3, in Adult Skeletal Muscle Fibers

Tiansheng Shen ^*, Yewei Liu ^*, Zoltán Cseresnyés ^*, Arie Hawkins ^*, William R. Randall , and Martin F. Schneider ^*

^* Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201

Submitted August 19, 2005; Revised January 6, 2006; Accepted January 12, 2006
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 because of activation of the Ca²⁺-dependent phosphatase calcineurin, resulting in nuclear factor of activated T-cells (NFAT) dephosphorylation and consequent exposure of its nuclear localization signal. Here, we find that unstimulated adult skeletal muscle fibers exhibit a previously unanticipated nucleocytoplasmic 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 they did not cause NFATc1 nuclear uptake in unstimulated fibers. We propose that two nuclear translocation pathways, one pathway mediated by calcineurin activation and NFAT dephosphorylation and the other pathway independent of calcineurin and possibly independent of NFAT dephosphorylation, determine the distribution of NFATc1 between cytoplasm and nuclei in adult skeletal muscle.

Abbreviations used: CK1, casein kinase 1; CsA, cyclosporin A; FDB, flexor digitorum brevis; GFP, green fluorescence protein; GSK, glycogen synthase kinase-3; HDAC4, histone deacetylase 4; JNK, c-Jun NH₂-terminal kinase; LMB, leptomycin B; mRFP, monomeric red fluorescent protein; NFAT, nuclear factor of activated T-cells; PKA, protein kinase A; p38, p38 MAPK.

Address correspondence to: Martin F. Schneider (mschneid{at}umaryland.edu).

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