A new role for the calcineurin/NFAT pathway in neonatal myosin heavy chain expression via the NFATc2/MyoD complex during mouse myogenesis

Development. 2013 Dec;140(24):4914-25. doi: 10.1242/dev.097428.


The calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway is involved in the modulation of the adult muscle fiber type, but its role in the establishment of the muscle phenotype remains elusive. Here, we show that the NFAT member NFATc2 cooperates with the basic helix-loop-helix transcription factor MyoD to induce the expression of a specific myosin heavy chain (MHC) isoform, the neonatal one, during embryogenesis. We found this cooperation to be crucial, as Myod/Nfatc2 double-null mice die at birth, with a dramatic reduction of the major neonatal MHC isoform normally expressed at birth in skeletal muscles, such as limb and intercostal muscles, whereas its expression is unaffected in myofibers mutated for either factor alone. Using gel shift and chromatin immunoprecipitation assays, we identified NFATc2 bound to the neonatal Mhc gene, whereas NFATc1 and NFATc3 would preferentially bind the embryonic Mhc gene. We provide evidence that MyoD synergistically cooperates with NFATc2 at the neonatal Mhc promoter. Altogether, our findings demonstrate that the calcineurin/NFAT pathway plays a new role in establishing the early muscle fiber type in immature myofibers during embryogenesis.

Keywords: Calcineurin; MyoD; Myogenesis; Myogenic regulatory factors; Myosin heavy chain; NFAT; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Calcineurin / metabolism*
  • Cell Line
  • Chlorocebus aethiops
  • Mice
  • Mice, Knockout
  • Muscle Development*
  • Muscle, Skeletal / embryology*
  • MyoD Protein / genetics
  • MyoD Protein / metabolism*
  • Myosin Heavy Chains / biosynthesis
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism*
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Promoter Regions, Genetic
  • Protein Isoforms / biosynthesis
  • Signal Transduction / immunology


  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Nfatc2 protein, mouse
  • Nfatc3 protein, mouse
  • Protein Isoforms
  • Calcineurin
  • Myosin Heavy Chains