Published online 16 April 2001. doi:10.1083/jcb.153.2.329
© The Rockefeller University Press,
0021-9525/2001//329 $5.00
The Journal of Cell Biology, Volume 153, Number 2,
, 2001 329-338
Regulation of the Growth of Multinucleated Muscle Cells by an Nfatc2-Dependent Pathway
Valerie Horsleya,
Bret B. Fridaya,
Sarah Mattesona,
Kristy Miller Kegleya,
Jonathan Gepharta, and
Grace K. Pavlatha
a Department of Pharmacology, Emory University, Atlanta, Georgia 30322
Emory University School of Medicine, Department of Pharmacology, Rm. 5027, O.W. Rollins Research Bldg., Atlanta, GA 30322.(404) 727-0365(404) 727-3353
gpavlat{at}emory.edu
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.
Key Words: NFATC2 myotube muscle growth nuclear number fusion
© 2001 The Rockefeller University Press
Abbreviations used in this paper: CSA, cross-sectional area; DM, differentiation medium; EMyHC, embryonic MyHC; MyHC, myosin heavy chain; NFAT, nuclear factor of activated T cells; RT, reverse transcription; TA, tibialis anterior.

CiteULike
Complore
Connotea
Del.icio.us
Digg
Facebook
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:
-
Karpurapu, M., Wang, D., Van Quyen, D., Kim, T.-K., Kundumani-Sridharan, V., Pulusani, S., Rao, G. N.
(2010). Cyclin D1 Is a Bona Fide Target Gene of NFATc1 and Is Sufficient in the Mediation of Injury-induced Vascular Wall Remodeling. J. Biol. Chem.
285: 3510-3523
[Abstract]
[Full Text]
-
Maitra, U., Parks, J. S., Li, L.
(2009). An Innate Immunity Signaling Process Suppresses Macrophage ABCA1 Expression through IRAK-1-Mediated Downregulation of Retinoic Acid Receptor {alpha} and NFATc2. Mol. Cell. Biol.
29: 5989-5997
[Abstract]
[Full Text]
-
Calabria, E., Ciciliot, S., Moretti, I., Garcia, M., Picard, A., Dyar, K. A., Pallafacchina, G., Tothova, J., Schiaffino, S., Murgia, M.
(2009). NFAT isoforms control activity-dependent muscle fiber type specification. Proc. Natl. Acad. Sci. USA
106: 13335-13340
[Abstract]
[Full Text]
-
Short, B.
(2009). Valerie Horsley: Getting under the skin. JCB
184: 466-467
[Full Text]
-
Cowling, B. S., McGrath, M. J., Nguyen, M.-A., Cottle, D. L., Kee, A. J., Brown, S., Schessl, J., Zou, Y., Joya, J., Bonnemann, C. G., Hardeman, E. C., Mitchell, C. A.
(2008). Identification of FHL1 as a regulator of skeletal muscle mass: implications for human myopathy. JCB
183: 1033-1048
[Abstract]
[Full Text]
-
Karpurapu, M., Wang, D., Singh, N. K., Li, Q., Rao, G. N.
(2008). NFATc1 Targets Cyclin A in the Regulation of Vascular Smooth Muscle Cell Multiplication during Restenosis. J. Biol. Chem.
283: 26577-26590
[Abstract]
[Full Text]
-
Rana, Z. A., Gundersen, K., Buonanno, A.
(2008). Activity-dependent repression of muscle genes by NFAT. Proc. Natl. Acad. Sci. USA
105: 5921-5926
[Abstract]
[Full Text]
-
van der Velden, J. L. J., Schols, A. M. W. J., Willems, J., Kelders, M. C. J. M., Langen, R. C. J.
(2008). Glycogen Synthase Kinase 3 Suppresses Myogenic Differentiation through Negative Regulation of NFATc3. J. Biol. Chem.
283: 358-366
[Abstract]
[Full Text]
-
Lara-Pezzi, E., Winn, N., Paul, A., McCullagh, K., Slominsky, E., Santini, M. P., Mourkioti, F., Sarathchandra, P., Fukushima, S., Suzuki, K., Rosenthal, N.
(2007). A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration. JCB
179: 1205-1218
[Abstract]
[Full Text]
-
Bondesen, B. A., Jones, K. A., Glasgow, W. C., Pavlath, G. K.
(2007). Inhibition of myoblast migration by prostacyclin is associated with enhanced cell fusion. FASEB J.
21: 3338-3345
[Abstract]
[Full Text]
-
Bryer, S. C., Koh, T. J.
(2007). The urokinase-type plasminogen activator receptor is not required for skeletal muscle inflammation or regeneration. Am. J. Physiol. Regul. Integr. Comp. Physiol.
293: R1152-R1158
[Abstract]
[Full Text]
-
Bush, C. R., Havens, J. M., Necela, B. M., Su, W., Chen, L., Yanagisawa, M., Anastasiadis, P. Z., Guerra, R., Luxon, B. A., Thompson, E. A.
(2007). Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor {gamma} and Calcium Signaling in Human Colorectal Cancer Cells. J. Biol. Chem.
282: 23387-23401
[Abstract]
[Full Text]
-
Schiaffino, S., Sandri, M., Murgia, M.
(2007). Activity-Dependent Signaling Pathways Controlling Muscle Diversity and Plasticity. Physiology
22: 269-278
[Abstract]
[Full Text]
-
Stupka, N., Schertzer, J. D., Bassel-Duby, R., Olson, E. N., Lynch, G. S.
(2007). Calcineurin-A{alpha} activation enhances the structure and function of regenerating muscles after myotoxic injury. Am. J. Physiol. Regul. Integr. Comp. Physiol.
293: R686-R694
[Abstract]
[Full Text]
-
Parsons, S. A., Millay, D. P., Sargent, M. A., Naya, F. J., McNally, E. M., Sweeney, H. L., Molkentin, J. D.
(2007). Genetic Disruption of Calcineurin Improves Skeletal Muscle Pathology and Cardiac Disease in a Mouse Model of Limb-Girdle Muscular Dystrophy. J. Biol. Chem.
282: 10068-10078
[Abstract]
[Full Text]
-
Jacquemin, V., Butler-Browne, G. S., Furling, D., Mouly, V.
(2007). IL-13 mediates the recruitment of reserve cells for fusion during IGF-1-induced hypertrophy of human myotubes. J. Cell Sci.
120: 670-681
[Abstract]
[Full Text]
-
O'Connor, R. S., Mills, S. T., Jones, K. A., Ho, S. N., Pavlath, G. K.
(2007). A combinatorial role for NFAT5 in both myoblast migration and differentiation during skeletal muscle myogenesis. J. Cell Sci.
120: 149-159
[Abstract]
[Full Text]
-
Fornaro, M., Burch, P. M., Yang, W., Zhang, L., Hamilton, C. E., Kim, J. H., Neel, B. G., Bennett, A. M.
(2006). SHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growth. JCB
175: 87-97
[Abstract]
[Full Text]
-
Jansen, K. M., Pavlath, G. K.
(2006). Mannose receptor regulates myoblast motility and muscle growth. JCB
174: 403-413
[Abstract]
[Full Text]
-
Borchers, A., Fonar, Y., Frank, D., Baker, J. C.
(2006). XNF-ATc3 affects neural convergent extension. Development
133: 1745-1755
[Abstract]
[Full Text]
-
Park, I.-H., Chen, J.
(2005). Mammalian Target of Rapamycin (mTOR) Signaling Is Required for a Late-stage Fusion Process during Skeletal Myotube Maturation. J. Biol. Chem.
280: 32009-32017
[Abstract]
[Full Text]
-
Oh, M., Rybkin, I. I., Copeland, V., Czubryt, M. P., Shelton, J. M., van Rooij, E., Richardson, J. A., Hill, J. A., De Windt, L. J., Bassel-Duby, R., Olson, E. N., Rothermel, B. A.
(2005). Calcineurin Is Necessary for the Maintenance but Not Embryonic Development of Slow Muscle Fibers. Mol. Cell. Biol.
25: 6629-6638
[Abstract]
[Full Text]
-
Schulze, M., Belema-Bedada, F., Technau, A., Braun, T.
(2005). Mesenchymal stem cells are recruited to striated muscle by NFAT/IL-4-mediated cell fusion. Genes Dev.
19: 1787-1798
[Abstract]
[Full Text]
-
Liu, Z., Zhang, C., Dronadula, N., Li, Q., Rao, G. N.
(2005). Blockade of Nuclear Factor of Activated T Cells Activation Signaling Suppresses Balloon Injury-induced Neointima Formation in a Rat Carotid Artery Model. J. Biol. Chem.
280: 14700-14708
[Abstract]
[Full Text]
-
Spangenburg, E. E.
(2005). SOCS-3 Induces Myoblast Differentiation. J. Biol. Chem.
280: 10749-10758
[Abstract]
[Full Text]
-
Lafuste, P., Sonnet, C., Chazaud, B., Dreyfus, P. A., Gherardi, R. K., Wewer, U. M., Authier, F.-J.
(2005). ADAM12 and {alpha}9{beta}1 Integrin Are Instrumental in Human Myogenic Cell Differentiation. Mol. Biol. Cell
16: 861-870
[Abstract]
[Full Text]
-
Liu, Z., Dronadula, N., Rao, G. N.
(2004). A Novel Role for Nuclear Factor of Activated T Cells in Receptor Tyrosine Kinase and G Protein-coupled Receptor Agonist-induced Vascular Smooth Muscle Cell Motility. J. Biol. Chem.
279: 41218-41226
[Abstract]
[Full Text]
-
McCullagh, K. J. A., Calabria, E., Pallafacchina, G., Ciciliot, S., Serrano, A. L., Argentini, C., Kalhovde, J. M., Lomo, T., Schiaffino, S.
(2004). NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching. Proc. Natl. Acad. Sci. USA
101: 10590-10595
[Abstract]
[Full Text]
-
Gonzalez Bosc, L. V., Wilkerson, M. K., Bradley, K. N., Eckman, D. M., Hill-Eubanks, D. C., Nelson, M. T.
(2004). Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation: ROLE OF CALCIUM, ENDOTHELIUM-DERIVED NITRIC OXIDE, AND cGMP-DEPENDENT PROTEIN KINASE. J. Biol. Chem.
279: 10702-10709
[Abstract]
[Full Text]
-
Sorensen, S. D., Nicole, O., Peavy, R. D., Montoya, L. M., Lee, C. J., Murphy, T. J., Traynelis, S. F., Hepler, J. R.
(2003). Common Signaling Pathways Link Activation of Murine PAR-1, LPA, and S1P Receptors to Proliferation of Astrocytes. Mol. Pharmacol.
64: 1199-1209
[Abstract]
[Full Text]
-
Parsons, S. A., Wilkins, B. J., Bueno, O. F., Molkentin, J. D.
(2003). Altered Skeletal Muscle Phenotypes in Calcineurin A{alpha} and A{beta} Gene-Targeted Mice. Mol. Cell. Biol.
23: 4331-4343
[Abstract]
[Full Text]
-
Pavlath, G. K., Dominov, J. A., Kegley, K. M., Miller, J. B.
(2003). Regeneration of Transgenic Skeletal Muscles with Altered Timing of Expression of the Basic Helix-Loop-Helix Muscle Regulatory Factor MRF4. Am. J. Pathol.
162: 1685-1691
[Abstract]
[Full Text]
-
Horsley, V., Pavlath, G. K.
(2003). Prostaglandin F2{alpha} stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway. JCB
161: 111-118
[Abstract]
[Full Text]
-
van Rooij, E., Doevendans, P. A., de Theije, C. C., Babiker, F. A., Molkentin, J. D., De Windt, L. J.
(2002). Requirement of Nuclear Factor of Activated T-cells in Calcineurin-mediated Cardiomyocyte Hypertrophy. J. Biol. Chem.
277: 48617-48626
[Abstract]
[Full Text]
-
Wilkins, B. J., De Windt, L. J., Bueno, O. F., Braz, J. C., Glascock, B. J., Kimball, T. F., Molkentin, J. D.
(2002). Targeted Disruption of NFATc3, but Not NFATc4, Reveals an Intrinsic Defect in Calcineurin-Mediated Cardiac Hypertrophic Growth. Mol. Cell. Biol.
22: 7603-7613
[Abstract]
[Full Text]
-
Vyas, D. R., Spangenburg, E. E., Abraha, T. W., Childs, T. E., Booth, F. W.
(2002). GSK-3beta negatively regulates skeletal myotube hypertrophy. Am. J. Physiol. Cell Physiol.
283: C545-C551
[Abstract]
[Full Text]
-
Mozdziak, P. E., Evans, J. J., McCoy, D. W.
(2002). Early Posthatch Starvation Induces Myonuclear Apoptosis in Chickens. J. Nutr.
132: 901-903
[Abstract]
[Full Text]
-
Horsley, V., Pavlath, G. K.
(2002). Nfat: ubiquitous regulator of cell differentiation and adaptation. JCB
156: 771-774
[Abstract]
[Full Text]
-
Dunn, S. E., Simard, A. R., Bassel-Duby, R., Williams, R. S., Michel, R. N.
(2001). Nerve Activity-dependent Modulation of Calcineurin Signaling in Adult Fast and Slow Skeletal Muscle Fibers. J. Biol. Chem.
276: 45243-45254
[Abstract]
[Full Text]
-
Horsley, V., Pavlath, G. K.
(2002). Nfat: ubiquitous regulator of cell differentiation and adaptation. JCB
156: 771-774
[Abstract]
[Full Text]