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Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway
V Horsley1, B B Friday, S Matteson
1Department of Pharmacology, Emory University, Atlanta, Georgia 30322, USA.
Abstract:
The nuclear factor of activated T cells (NFAT) family of transcription factors regulates the development and differentiation of several tissue types. Here, we examine the role of NFATC2 in skeletal muscle by analyzing adult NFATC2(-/)- mice. These mice exhibit reduced muscle size due to a decrease in myofiber cross-sectional area, suggesting that growth is blunted. Muscle growth was examined during regeneration after injury, wherein NFATC2-null myofibers form normally but display impaired growth. The growth defect is intrinsic to muscle cells, since the lack of NFATC2 in primary muscle cultures results in reduced cell size and myonuclear number in myotubes. Retroviral-mediated expression of NFATC2 in the mutant cells rescues this cellular phenotype. Myonuclear number is similarly decreased in NFATC2(-/)- mice. Taken together, these results implicate a novel role for NFATC2 in skeletal muscle growth. We demonstrate that during growth of multinucleated muscle cells, myoblasts initially fuse to form myotubes with a limited number of nuclei and that subsequent nuclear addition and increases in myotube size are controlled by a molecular pathway regulated by NFATC2.
Insights
Nuclear factor of activated T cells 2 (NFATC2) is crucial for skeletal muscle growth. NFATC2 deficiency in mice leads to smaller muscles and impaired regeneration, highlighting its role in myotube development.
Area of Science:
- Molecular Biology
- Cell Biology
- Physiology
Background:
- The nuclear factor of activated T cells (NFAT) family regulates tissue development.
- NFATc2 (NFATC2) is a key transcription factor within this family.
- Its specific role in skeletal muscle growth requires further elucidation.
Purpose of the Study:
- To investigate the function of NFATC2 in adult skeletal muscle.
- To determine the impact of NFATC2 deficiency on muscle size and regeneration.
- To elucidate the cellular mechanisms underlying NFATC2-mediated muscle growth.
Main Methods:
- Analysis of adult NFATC2 knockout (NFATC2-/-) mice.
- Assessment of myofiber cross-sectional area and muscle size.
- Examination of muscle regeneration post-injury.
- In vitro studies using primary muscle cell cultures.
- Rescue experiments with retroviral NFATC2 expression.
Main Results:
- NFATC2-/- mice exhibited reduced muscle size and myofiber cross-sectional area.
- NFATC2-null myofibers showed normal formation but impaired growth during regeneration.
- Primary muscle cultures lacking NFATC2 displayed reduced cell size and myonuclear number.
- Retroviral NFATC2 expression rescued the cellular phenotype in mutant cells.
- A decrease in myonuclear number was observed in NFATC2-/- mice.
Conclusions:
- NFATC2 plays a novel and essential role in skeletal muscle growth.
- The growth defect associated with NFATC2 deficiency is intrinsic to muscle cells.
- NFATC2 regulates subsequent nuclear addition and myotube size increase during muscle cell growth.