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Mice lacking calsarcin-1 are sensitized to ... - UT Southwestern

Mice lacking calsarcin-1 are sensitized to ... - UT Southwestern

Mice lacking calsarcin-1 are sensitized to ... - UT

ARTICLES© 2004 Nature Publishing Group http://www.nature.com/naturemedicineMice lacking calsarcin-1 are sensitized to calcineurinsignaling and show accelerated cardiomyopathy inresponse to pathological biomechanical stressNorbert Frey 1,2,7 ,Tomasa Barrientos 1,6,7 ,John M Shelton 5,6 ,Derk Frank 2 ,Hartmut Rütten 4 ,Doris Gehring 4 ,Christian Kuhn 2 ,Matthias Lutz 2 ,Beverly Rothermel 5 ,Rhonda Bassel-Duby 1 ,James A Richardson 3 ,Hugo A Katus 2 ,Joseph A Hill 1,5,6 & Eric N Olson 1,6Signaling by the calcium-dependent phosphatase calcineurin profoundly influences the growth and gene expression of cardiac andskeletal muscle. Calcineurin binds to calsarcins, a family of muscle-specific proteins of the sarcomeric Z-disc, a focal point in thepathogenesis of human cardiomyopathies. We show that calsarcin-1 negatively modulates the functions of calcineurin, such thatcalcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1. As a consequence of inappropriatecalcineurin activation, mice with a null mutation in calsarcin-1 showed an excess of slow skeletal muscle fibers. The absence ofcalsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth responseto pressure overload. In contrast, cardiac adaptation to other hypertrophic stimuli, such as chronic catecholamine stimulation orexercise, was not affected. These findings show important roles for calsarcins as modulators of calcineurin signaling and thetransmission of a specific subset of stress signals leading to cardiac remodeling in vivo.The calcium/calmodulin-dependent phosphatase calcineurin transducescalcium signals that lead to remodeling of skeletal and cardiacmuscle in response to physiological and pathological stimuli 1,2 .Inaddition to several cytoplasmic substrates, calcineurin dephosphorylatesmembers of the nuclear factor of activated T-cell (NFAT) familyof transcription factors, resulting in their nuclear translocation andactivation of target genes 3,4 .In the heart, calcineurin is activated bydiverse agonists that promote cardiomyocyte growth 5 ,as well as alterationsof sarcomere integrity 6 and mechanical stress 7 .Overexpressionof a constitutively active form of calcineurin leads to cardiac hypertrophyand cardiomyopathy 5 ,as well as the reactivation of a fetal cardiacgene program, which includes genes whose products controlcontractility, calcium handling and energy metabolism. Conversely,pharmacological inhibition of calcineurin 8 or overexpression ofinhibitory proteins such as MCIP (modulatory calcineurin-interactingprotein) 9,10 ,Cabin/Cain or AKAP79 (ref. 11) attenuates the cardiacgrowth that results from pathological stimuli.In skeletal muscle, contractile and metabolic properties of musclefibers are dictated by the pattern of calcium signaling resulting frommotor innervation and activity. In response to sustained, low-amplitudecalcium signals, muscle fibers adopt a slow-twitch phenotypecharacterized by an oxidative metabolism, whereas high-frequencycalcium signaling favors the appearance of fast, glycolytic fibers 12 .Overexpression of calcineurin in skeletal muscle promotes the conversionof fast to slow fibers, whereas inhibition of calcineurinreverses this process 13,14 .Previously, we described a family of calcineurin-interacting proteins,calsarcins, expressed exclusively in striated muscle 15,16 .Calsarcin-1 is the only member of the calsarcin family expressed in theadult heart and slow-twitch skeletal muscle, whereas calsarcin-2 (alsocalled FATZ and myozenin) and -3 are expressed in fast-twitch muscle15–18 .Calsarcins colocalize with calcineurin at the Z-disc, wherethey also interact with several sarcomeric proteins, includingα-actinin, γ-filamin, T-Cap/telethonin and ZASP/Cypher/Oracle.Notably, the Z-disc has been proposed not only to crosslink thin filaments,but also to be a focal point for signaling in striated muscle 19–21 .Here we show that calcineurin signaling is enhanced in striatedmuscles of mice lacking the Myoz2 gene, which encodes calsarcin-1.Consistent with the role of calcineurin as a positive regulator of theslow fiber phenotype, calsarcin-1-deficient mice showed an excess ofslow muscle fibers. Despite the absence of cardiac hypertrophy,unstressed calsarcin-1-deficient mice showed marked activation ofthe fetal gene program, which typically accompanies pathologicalhypertrophy. Furthermore, these mice developed exaggerated hypertrophyin response to calcineurin activation or pressure overload, butnot other stimuli. These findings show a key role for calsarcin-1 in1 Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA. 2 Department ofInternal Medicine III University of Heidelberg, IFN410, 69120 Heidelberg, Germany. 3 Pathology, University of Texas Southwestern Medical Center, 5323 Harry HinesBoulevard, Dallas, Texas 75390-9072, USA. 4 DG Cardiovascular, Aventis Pharma GmbH, 65926 Frankfurt, Germany. 5 Department of Internal Medicine, University ofTexas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8573, USA. 6 Donald W. Reynolds Cancer Center, University of TexasSouthwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA. 7 These authors contributed equally to this work. Correspondenceshould be addressed to E.N.O. (eric.olson@utsouthwestern.edu) or N.F. (norbert.frey@med.uni-heidelberg.de).Published 14 November 2004; doi:10.1038/nm11321336 VOLUME 10 | NUMBER 11 | NOVEMBER 2004 NATURE MEDICINE

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