NFAT isoforms control activity-dependent muscle fiber type specification.
The intracellular signals that convert fast and slow motor neuron activity into muscle fiber type specific transcriptional programs have only been partially defined. The calcium/calmodulin-dependent phosphatase calcineurin (Cn) has been shown to mediate the transcriptional effects of motor neuron activity, but precisely how 4 distinct muscle fiber types are composed and maintained in response to activity is largely unknown. Here, we show that 4 nuclear factor of activated T cell (NFAT) family members act coordinately downstream of Cn in the specification of muscle fiber types. We analyzed the role of NFAT family members in vivo by transient transfection in skeletal muscle using a loss-of-function approach by RNAi. Our results show that, depending on the applied activity pattern, different combinations of NFAT family members translocate to the nucleus contributing to the transcription of fiber type specific genes. We provide evidence that the transcription of slow and fast myosin heavy chain (MyHC) genes uses different combinations of NFAT family members, ranging from MyHC-slow, which uses all 4 NFAT isoforms, to MyHC-2B, which only uses NFATc4. Our data contribute to the elucidation of the mechanisms whereby activity can modulate the phenotype and performance of skeletal muscle.
Calabria
Elisa
E
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
Ciciliot
Stefano
S
Moretti
Irene
I
Garcia
Marta
M
Picard
Anne
A
Dyar
Kenneth A
KA
Pallafacchina
Giorgia
G
Tothova
Jana
J
Schiaffino
Stefano
S
Murgia
Marta
M
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004560:Electricity; D020868:Gene Silencing; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009928:Organ Specificity; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration; D014158:Transcription, Genetic
D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D018995:Myosin Heavy Chains