Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 32, Pages 13335-13340Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812911106
Keywords
skeletal muscle; calcineurin; myosin; gene regulation
Categories
Funding
- European Commission [NoE MYORES, LSHG-CT-2004-511978, IP EXGENESIS, LSHM-CT-2004-005272]
- Ministero dell'Universita e della Ricerca Scientifica e Technologica of Italy [PRIN 2006]
- Telethon [GGP04227]
- Agenzia Spaziale Italiana Osteoporosis and Muscular Atrophy
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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.
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