NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching.

Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0027-8424 (Print) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE

Original Publication: Washington, DC : National Academy of Sciences

Gene Expression Regulation* ; Nuclear Proteins*; DNA-Binding Proteins/*metabolism ; Motor Neurons/*metabolism ; Muscle, Skeletal/*physiology ; Myosins/*metabolism ; Transcription Factors/*metabolism; Animals ; Calcineurin/genetics ; Calcineurin/metabolism ; DNA-Binding Proteins/genetics ; Electric Stimulation ; Genes, Reporter ; In Vitro Techniques ; Male ; Muscle Fibers, Fast-Twitch/cytology ; Muscle Fibers, Fast-Twitch/physiology ; Muscle Fibers, Slow-Twitch/cytology ; Muscle Fibers, Slow-Twitch/physiology ; Muscle, Skeletal/cytology ; Muscle, Skeletal/innervation ; Myosins/genetics ; NFATC Transcription Factors ; Oligopeptides/metabolism ; Rats ; Rats, Wistar ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Signal Transduction/physiology ; Transcription Factors/genetics

Calcineurin (Cn) signaling has been implicated in nerve activity-dependent fiber type specification in skeletal muscle, but the downstream effector pathway has not been established. We have investigated the role of the transcription factor nuclear factor of activated T cells (NFAT), a major target of Cn, by using an in vivo transfection approach in regenerating and adult rat muscles. NFAT transcriptional activity was monitored with two different NFAT-dependent reporters and was found to be higher in slow compared to fast muscles. NFAT activity is decreased by denervation in slow muscles and is increased by electrostimulation of denervated muscles with a tonic low-frequency impulse pattern, mimicking the firing pattern of slow motor neurons, but not with a phasic high-frequency pattern typical of fast motor neurons. To determine the role of NFAT, we transfected regenerating and adult rat muscles with a plasmid coding for VIVIT, a specific peptide inhibitor of Cn-mediated NFAT activation. VIVIT was found to block the expression of slow myosin heavy chain (MyHC-slow) induced by slow motor neuron activity in regenerating slow soleus muscle and to inhibit the expression of MyHC-slow transcripts and the activity of a MyHC-slow promoter in adult soleus. The role of NFAT was confirmed by the finding that a constitutively active NFATc1 mutant stimulates the MyHC-slow, inhibits the fast MyHC-2B promoter in adult fast muscles, and induces MyHC-slow expression in regenerating muscles. These results support the notion that Cn-NFAT signaling acts as a nerve activity sensor in skeletal muscle in vivo and controls nerve activity-dependent myosin switching.

Erratum in: Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2424252121. doi: 10.1073/pnas.2424252121. (PMID: 39680777)

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0 (DNA-Binding Proteins)
0 (NFATC Transcription Factors)
0 (Nuclear Proteins)
0 (Oligopeptides)
0 (Recombinant Fusion Proteins)
0 (Transcription Factors)
0 (VIVIT peptide)
EC 3.1.3.16 (Calcineurin)
EC 3.6.4.1 (Myosins)

Date Created: 20040713 Date Completed: 20040826 Latest Revision: 20241216

20241217

PMC489979

10.1073/pnas.0308035101

15247427