title: Genetic disruption of calcineurin improves skeletal muscle pathology and cardiac disease in a mouse model of limb-girdle muscular dystrophy.
abstract: Calcineurin (Cn) is a Ca(2+)/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 delta-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 Abeta (CnAbeta) 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.
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Parsons
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039; Department of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 45267.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Millay
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sargent
authors.affiliation: Department of Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Naya
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039. Electronic address: jeff.molkentin@cchmc.org.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics*; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics
chemical_list: D049031:Sarcoglycans; D019703:Calcineurin