title: The calcineurin-NFAT pathway controls activity-dependent circadian gene expression in slow skeletal muscle.
abstract: OBJECTIVE
  Physical activity and circadian rhythms are well-established determinants of human health and disease, but the relationship between muscle activity and the circadian regulation of muscle genes is a relatively new area of research. It is unknown whether muscle activity and muscle clock rhythms are coupled together, nor whether activity rhythms can drive circadian gene expression in skeletal muscle.
  
  
  METHODS
  We compared the circadian transcriptomes of two mouse hindlimb muscles with vastly different circadian activity patterns, the continuously active slow soleus and the sporadically active fast tibialis anterior, in the presence or absence of a functional skeletal muscle clock (skeletal muscle-specific Bmal1 KO). In addition, we compared the effect of denervation on muscle circadian gene expression.
  
  
  RESULTS
  We found that different skeletal muscles exhibit major differences in their circadian transcriptomes, yet core clock gene oscillations were essentially identical in fast and slow muscles. Furthermore, denervation caused relatively minor changes in circadian expression of most core clock genes, yet major differences in expression level, phase and amplitude of many muscle circadian genes.
  
  
  CONCLUSIONS
  We report that activity controls the oscillation of around 15% of skeletal muscle circadian genes independently of the core muscle clock, and we have identified the Ca(2+)-dependent calcineurin-NFAT pathway as an important mediator of activity-dependent circadian gene expression, showing that circadian locomotor activity rhythms drive circadian rhythms of NFAT nuclear translocation and target gene expression.
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Dyar
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ciciliot
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy ; Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: Guidantonio Malagoli
authors.initials: GM
authors.lastname: Tagliazucchi
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy ; Institute of Neurosciences, Consiglio Nazionale delle Ricerche (CNR), Padova, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pallafacchina
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Jana
authors.initials: J
authors.lastname: Tothova
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Argentini
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Agatea
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy.
authors.forename: Reimar
authors.initials: R
authors.lastname: Abraham
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany.
authors.forename: Miika
authors.initials: M
authors.lastname: Ahdesmäki
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Forcato
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy ; Institute of Neurosciences, Consiglio Nazionale delle Ricerche (CNR), Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Schiaffino
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy ; Department of Biomedical Sciences, University of Padova, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
keywords: Activity; Circadian; NFAT; Skeletal muscle