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Molecular and Cellular Biology, August 2005, p. 6629-6638, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6629-6638.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Calcineurin Is Necessary for the Maintenance but Not Embryonic Development of Slow Muscle Fibers

Misook Oh,1 Igor I. Rybkin,2 Victoria Copeland,1 Michael P. Czubryt,2 John M. Shelton,1 Eva van Rooij,4 James A. Richardson,2,3 Joseph A. Hill,1,2 Leon J. De Windt,4 Rhonda Bassel-Duby,2 Eric N. Olson,2 and Beverly A. Rothermel1*

Departments of Internal Medicine,1 Molecular Biology,2 Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,3 Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Utrecht 3584 CT, The Netherlands4

Received 5 February 2005/ Returned for modification 1 March 2005/ Accepted 12 May 2005

Skeletal muscles are a mosaic of slow and fast twitch myofibers. During embryogenesis, patterns of fiber type composition are initiated that change postnatally to meet physiological demand. To examine the role of the protein phosphatase calcineurin in the initiation and maintenance of muscle fiber types, we used a "Flox-ON" approach to obtain muscle-specific overexpression of the modulatory calcineurin-interacting protein 1 (MCIP1/DSCR1), an inhibitor of calcineurin. Myo-Cre transgenic mice with early skeletal muscle-specific expression of Cre recombinase were used to activate the Flox-MCIP1 transgene. Contractile components unique to type 1 slow fibers were absent from skeletal muscle of adult Myo-Cre/Flox-MCIP1 mice, whereas oxidative capacity, myoglobin content, and mitochondrial abundance were unaltered. The soleus muscles of Myo-Cre/Flox-MCIP1 mice fatigued more rapidly than the wild type as a consequence of the replacement of the slow myosin heavy chain MyHC-1 with a fast isoform, MyHC-2A. MyHC-1 expression in Myo-Cre/Flox-MCIP1 embryos and early neonates was normal. These results demonstrate that developmental patterning of slow fibers is independent of calcineurin, while the maintenance of the slow-fiber phenotype in the adult requires calcineurin activity.

* Corresponding author. Mailing address: University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390. Phone: (214) 648-7428. Fax: (214) 648-1450. E-mail: Beverly.Rothermel{at}utsouthwestern.edu.

Molecular and Cellular Biology, August 2005, p. 6629-6638, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6629-6638.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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