title: Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress.
abstract: Signaling by the calcium-dependent phosphatase calcineurin profoundly influences the growth and gene expression of cardiac and skeletal muscle. Calcineurin binds to calsarcins, a family of muscle-specific proteins of the sarcomeric Z-disc, a focal point in the pathogenesis of human cardiomyopathies. We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1. As a consequence of inappropriate calcineurin activation, mice with a null mutation in calsarcin-1 showed an excess of slow skeletal muscle fibers. The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload. In contrast, cardiac adaptation to other hypertrophic stimuli, such as chronic catecholamine stimulation or exercise, was not affected. These findings show important roles for calsarcins as modulators of calcineurin signaling and the transmission of a specific subset of stress signals leading to cardiac remodeling in vivo.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA. norbert.frey@med.uni-heidelberg.de
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.forename: Tomasa
authors.initials: T
authors.lastname: Barrientos
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: Derk
authors.initials: D
authors.lastname: Frank
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rütten
authors.forename: Doris
authors.initials: D
authors.lastname: Gehring
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhn
authors.forename: Matthias
authors.initials: M
authors.lastname: Lutz
authors.forename: Beverly
authors.initials: B
authors.lastname: Rothermel
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D009202:Cardiomyopathies / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004452:Echocardiography; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010805:Physical Conditioning, Animal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012518:Sarcomeres / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000378:metabolism; D001616:beta-Galactosidase
chemical_list: D000318:Adrenergic beta-Agonists; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D019703:Calcineurin; D001616:beta-Galactosidase; D007545:Isoproterenol