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J. Biol. Chem., Vol. 276, Issue 48, 45243-45254, November 30, 2001
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From the This study tested the hypothesis that calcineurin
signaling is modulated in skeletal muscle cells by fluctuations
in nerve-mediated activity. We show that dephosphorylation of NFATc1,
MEF2A, and MEF2D transcription factors by calcineurin in all muscle
types is dependent on nerve activity and positively correlated with muscle usage under normal weightbearing conditions. With increased nerve-mediated activity, calcineurin dephosphorylation of these targets
was found to be potentiated in a way that paralleled the higher muscle
activation profiles associated with functional overload or nerve
electrical stimulation conditions. We also establish that muscle
activity must be sustained above native levels for calcineurin-dependent dephosphorylation of MEF2A and MEF2D
to be transduced into an increase in MEF2 transcriptional function, suggesting that calcineurin cooperates with other activity-linked events to signal via these proteins. Finally, examination of individual fiber responses to overload and nerve electrical stimulation revealed that calcineurin-MEF2 signaling occurs in all fiber types but most
readily in fibers that are normally least active (i.e.
those expressing IIx and IIb myosin heavy chain (MHC)), suggesting that signaling via this phosphatase is also dependent upon the
activation history of the muscle cell.
Nerve Activity-dependent Modulation of
Calcineurin Signaling in Adult Fast and Slow Skeletal Muscle
Fibers*
§¶,¶,
,, and§**
Neuromuscular Research Laboratory,
Department of Chemistry and Biochemistry, Laurentian University,
Sudbury, Ontario P3E 2C6, Canada, the Department of Internal
Medicine, University of Texas Southwestern Medical Center, Dallas,
Texas 75390, and the § Faculty of Health Sciences,
University of Western Ontario, London, Ontario N6A 3K7, Canada
*
This work was supported in part by grants from the Natural
Sciences and Engineering Research Council of Canada (to R. N. M.) and the National Institutes of Health (to R. S. W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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