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Open Access Publications from the University of California

NFATc1 controls skeletal muscle fiber type and is a negative regulator of MyoD transcriptional activity

  • Author(s): Ehlers Stewart, Melissa Laura
  • Advisor(s): Black, Brian L
  • et al.

The NFAT family of transcription factors regulates cell differentiation programs in a variety of cellular contexts, including immune cell activation, cardiac valve development, osteoclast differentiation, and fiber type in skeletal muscle. NFAT proteins are activated by the phosphatase calcineurin in response to increases in intracellular calcium levels, and can function as either activators or repressors, depending on co-factor interactions. Four of the five known NFAT transcription factors are expressed in skeletal muscle, of which NFATc2 and NFATc3 have a known function in skeletal muscle in vivo. However, studies interrogating the role of NFATc1 in skeletal muscle in vivo have been limited because Nfatc1-null mice die around E12.5 due to cardiac valve defects. We identified a novel function for NFATc1 in skeletal muscle as a repressor of the skeletal muscle specific bHLH transcription factor MyoD. We found that NFATc1, but not other NFAT isoforms, inhibits MyoD transactivation function. We found that NFATc1 physically interacts with MyoD via the N-terminal transactivation domain of MyoD and inhibits MyoD-mediated conversion of C3H10T1/2 fibroblasts into myosin expressing myotubes. We show that, and that NFATc1 is able to inhibit the transactivation ability of MyoD. To further verify NFATc1 repression of MyoD and to study the role of NFATc1 in vivo, we used Cre-Lox technology to generate a skeletal-muscle specific nfatc1 knockout mouse (nfatc1SkM-KO). We show that NFATc1 controls skeletal muscle fiber type composition in adult mice. The balance between Type I (slow) and Type II (fast) myofibers is altered in mice lacking nfatc1, with these mice exhibiting an increase in the number of Type II (fast) myofibers compared to wild type mice. In addition, we found that NFATc1 is required for proper fiber type switching of myofibers from the fast-to-slow fiber type phenotype in response to endurance exercise training. Finally, we examined the expression levels of several known MyoD target genes in muscle of nfatc1 SkM-KO mice, and found that the majority of genes analyzed are upregulated, providing in vivo support of our findings that NFATc1 negatively regulates MyoD. We propose a model whereby NFATc1 represses MyoD transactivation ability, at least in part, to promote the slow fiber phenotype through repression of fast fiber genes regulated by MyoD.

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