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*Department of Pharmacology and
The widely used immunosuppressant cyclosporine A (CSA) blocks
nuclear translocation of the transcription factor, NF-AT (nuclear factor of activated T cells), preventing its activity. mRNA for several
NF-AT isoforms has been shown to exist in cells outside of the immune
system, suggesting a possible mechanism for side effects associated
with CSA treatment. In this study, we demonstrate that CSA inhibits
biochemical and morphological differentiation of skeletal muscle cells
while having a minimal effect on proliferation. Furthermore, in vivo
treatment with CSA inhibits muscle regeneration after induced trauma in
mice. These results suggest a role for NF-AT-mediated transcription
outside of the immune system. In subsequent experiments, we examined
the activation and cellular localization of NF-AT in skeletal muscle
cells in vitro. Known pharmacological inducers of NF-AT in lymphoid
cells also stimulate transcription from an NF-AT-responsive reporter
gene in muscle cells. Three isoforms of NF-AT (NF-ATp, c, and 4/x/c3)
are present in the cytoplasm of muscle cells at all stages of
myogenesis tested. However, each isoform undergoes calcium-induced
nuclear translocation from the cytoplasm at specific stages of muscle
differentiation, suggesting specificity among NF-AT isoforms in gene
regulation. Strikingly, one isoform (NF-ATc) can preferentially
translocate to a subset of nuclei within a single multinucleated
myotube. These results demonstrate that skeletal muscle cells
express functionally active NF-AT proteins and that the nuclear
translocation of individual NF-AT isoforms, which is essential for the
ability to coordinate gene expression, is influenced markedly by the
differentiation state of the muscle cell.
MD/Ph.D
Program, Emory University School of Medicine, Atlanta, Georgia 30322
Corresponding author.
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