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Originally published In Press as doi:10.1074/jbc.M313800200 on April 13, 2004
J. Biol. Chem., Vol. 279, Issue 25, 26192-26200, June 18, 2004
Genetic Loss of Calcineurin Blocks Mechanical Overload-induced Skeletal Muscle Fiber Type Switching but Not Hypertrophy*
Stephanie A. Parsons  ,
Douglas P. Millay,
Benjamin J. Wilkins,
Orlando F. Bueno,
Gretchen L. Tsika¶,
Joel R. Neilson||,
Christine M. Liberatore,
Katherine E. Yutzey,
Gerald R. Crabtree||,
Richard W. Tsika¶, and
Jeffery D. Molkentin**
From the
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, the Department of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 45267, the ¶Department of Biochemistry, School of Medicine, University of Missouri, Columbia, Missouri 65211, and the ||Departments of Pathology and Developmental Biology, Howard Hughes Medical Institute, Stanford University Medical School, Palo Alto, California 94305
The serine/threonine phosphatase calcineurin is an important regulator of calcium-activated intracellular responses in eukaryotic cells. In higher eukaryotes, calcium/calmodulin-mediated activation of calcineurin facilitates direct dephosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T-cells (NFAT). Recently, controversy has surrounded the role of calcineurin in mediating skeletal muscle cell hypertrophy. Here we examined the ability of calcineurin-deficient mice to undergo skeletal muscle hypertrophic growth following mechanical overload (MOV) stimulation or insulin-like growth factor-1 (IGF-1) stimulation. Two distinct models of calcineurin deficiency were employed: calcineurin A gene-targeted mice, which show a  50% reduction in total calcineurin, and calcineurin B1-LoxP-targeted mice crossed with a myosin light chain 1f cre knock-in allele, which show a greater than 80% loss of total calcineurin only in skeletal muscle. Calcineurin A-/- and calcineurin B1-LoxP(fl/fl)-MLC-cre mice show essentially no defects in muscle growth in response to IGF-1 treatment or MOV stimulation, although calcineurin A-/- mice show a basal defect in total fiber number in the plantaris and a mild secondary reduction in growth, consistent with a developmental defect in myogenesis. Both groups of gene-targeted mice show normal increases in Akt activation following MOV or IGF-1 stimulation. However, overload-mediated fiber-type switching was dramatically impaired in calcineurin B1-LoxP(fl/fl)-MLC-cre mice. NFAT-luciferase reporter transgenic mice failed to show a correlation between IGF-1- or MOV-induced hypertrophy and calcineurin-NFAT-dependent signaling in vivo. We conclude that calcineurin expression is important during myogenesis and fiber-type switching, but not for muscle growth in response to hypertrophic stimuli.
Received for publication, December 17, 2003
, and in revised form, April 2, 2004.
* This work was supported by grants from the National Institutes of Health and the Muscular Dystrophy Association (to J. D. M.) and a National Institutes of Health Training Grant 5T32 HL07382 (to S. A. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
** To whom correspondence should be addressed: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039. E-mail: jeff.molkentin{at}cchmc.org.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
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