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First published online 28 March 2006
doi: 10.1242/jcs.02875

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NFATc1 nucleocytoplasmic shuttling is controlled by nerve activity in skeletal muscle

Jana Tothova^1,2,*, Bert Blaauw^1,2,3,*, Giorgia Pallafacchina^1,2,*, Rüdiger Rudolf^1,2, Carla Argentini^1,2, Carlo Reggiani^3,4 and Stefano Schiaffino^1,2,4,

¹ Department of Biomedical Sciences, University of Padova, Padova, Italy
² Venetian Institute of Molecular Medicine (VIMM), Padova, Italy
³ Department of Anatomy and Physiology, University of Padova, Padova, Italy
⁴ CNR Institute of Neurosciences, University of Padova, Padova, Italy

Author for correspondence (e-mail: stefano.schiaffino{at}unipd.it)

Accepted 4 January 2006

Calcineurin-NFAT signaling has been shown to control activity-dependent muscle gene regulation and induce a program of gene expression typical of slow oxidative muscle fibers. Following Ca²⁺-calmodulin stimulation, calcineurin dephosphorylates NFAT proteins and induces their translocation into the nucleus. However, NFAT nuclear translocation has never been investigated in skeletal muscle in vivo. To determine whether NFATc1 nucleocytoplasmic shuttling depends on muscle activity, we transfected fast and slow mouse muscles with plasmids coding for an NFATc1-GFP fusion protein. We found that NFATc1-GFP has a predominantly cytoplasmic localization in the fast tibialis anterior muscle but a predominantly nuclear localization in the slow soleus muscle, with a characteristic focal intranuclear distribution. Two hours of complete inactivity, induced by denervation or anaesthesia, cause NFATc1 export out of the nucleus in soleus muscle fibers, whereas electrostimulation of tibialis anterior with a low-frequency tonic impulse pattern, mimicking the firing pattern of slow motor neurons, causes NFATc1 nuclear translocation. The activity-dependent nuclear import and export of NFATc1 is a rapid event, as visualized directly in vivo by two-photon microscopy. The calcineurin inhibitor cain/cabin1 causes nuclear export of NFATc1 both in normal soleus and stimulated tibialis anterior muscle. These findings support the notion that in skeletal muscle NFATc1 is a calcineurin-dependent nerve activity sensor.

Key words: Fast and slow skeletal muscles, NFAT, Nuclear translocation, Calcineurin, Nerve activity, Electrostimulation

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