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J. Biol. Chem., Vol. 282, Issue 13, 10068-10078, March 30, 2007

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Genetic Disruption of Calcineurin Improves Skeletal Muscle Pathology and Cardiac Disease in a Mouse Model of Limb-Girdle Muscular Dystrophy^*

Stephanie A. Parsons¹, Douglas P. Millay, Michelle A. Sargent, Francisco J. Naya^¶, Elizabeth M. McNally^||, H. Lee Sweeney^**, and Jeffery D. Molkentin²

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 Biology, Boston University, Boston, Massachusetts 02215, the ^||Department of Medicine, University of Chicago, Chicago, Illinois 60637, and the ^**Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Calcineurin (Cn) is a Ca²⁺/calmodulin-dependent serine/threonine phosphatase that regulates differentiation-specific gene expression in diverse tissues, including the control of fiber-type switching in skeletal muscle. Recent studies have implicated Cn signaling in diminishing skeletal muscle pathogenesis associated with muscle injury or disease-related muscle degeneration. For example, use of the Cn inhibitor cyclosporine A has been shown to delay muscle regeneration following toxin-induced injury and inhibit regeneration in the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. In contrast, transgenic expression of an activated mutant of Cn in skeletal muscle was shown to increase utrophin expression and reduce overall disease pathology in mdx mice. Here we examine the effect of altered Cn activation in the context of the -sarcoglycan-null (scgd^-/-) mouse model of limb-girdle muscular dystrophy. In contrast to results discussed in mdx mice, genetic deletion of a loxP-targeted calcineurin B1 (CnB1) gene using a skeletal muscle-specific cre allele in the scgd^-/- background substantially reduced skeletal muscle degeneration and histopathology compared with the scgd^-/- genotype alone. A similar regression in scgd-dependent disease manifestation was also observed in calcineurin A (CnA) gene-targeted mice in both skeletal muscle and heart. Conversely, increased Cn expression using a muscle-specific transgene increased cardiac fibrosis, decreased cardiac ventricular shortening, and increased muscle fiber loss in the quadriceps. Our results suggest that inhibition of Cn may benefit select types of muscular dystrophy.

Received for publication, October 4, 2006 , and in revised form, January 12, 2007.

^* This work was supported by a grant from the National Institutes of Health (to J. D. M.). 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.

¹ Supported by training grants from the National Institutes of Health Grants 5T32HL007752 and 1T32AR053461-01. Current address: Wyeth Research, Collegeville, PA 19426.

² Established Investigator of the American Heart Association. To whom correspondence should be addressed: 3333 Burnet Ave., Cincinnati, OH 45229. Fax: 513-636-5958; E-mail: jeff.molkentin{at}cchmc.org.

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