title: Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload.
abstract: Integrins are adhesive, signaling, and mechanotransduction proteins. Talin (Tln) activates integrins and links it to the actin cytoskeleton. Vertebrates contain two talin genes, tln1 and tln2. How Tln1 and Tln2 function in cardiac myocytes (CMs) is unknown. Tln1 and Tln2 expression were evaluated in the normal embryonic and adult mouse heart as well as in control and failing human adult myocardium. Tln1 function was then tested in the basal and mechanically stressed myocardium after cardiomyocyte-specific excision of the Tln1 gene. During embryogenesis, both Tln forms are highly expressed in CMs, but in the mature heart Tln2 becomes the main Tln isoform, localizing to the costameres. Tln1 expression is minimal in the adult CM. With pharmacological and mechanical stress causing hypertrophy, Tln1 is up-regulated in CMs and is specifically detected at costameres, suggesting its importance in the compensatory response to CM stress. In human failing heart, CM Tln1 also increases compared with control samples from normal functioning myocardium. To directly test Tln1 function in CMs, we generated CM-specific Tln1 knock-out mice (Tln1cKO). Tln1cKO mice showed normal basal cardiac structure and function but when subjected to pressure overload showed blunted hypertrophy, less fibrosis, and improved cardiac function versus controls. Acute responses of ERK1/2, p38, Akt, and glycogen synthase kinase 3 after mechanical stress were strongly blunted in Tln1cKO mice. Given these results, we conclude that Tln1 and Tln2 have distinct functions in the myocardium. Our data show that reduction of CM Tln1 expression can lead to improved cardiac remodeling following pressure overload.
authors.affiliation: Veterans Administration Healthcare, San Diego, California 92161, USA.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Manso
authors.forename: Ruixia
authors.initials: R
authors.lastname: Li
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Monkley
authors.forename: Nathalia M
authors.initials: NM
authors.lastname: Cruz
authors.forename: Shannon
authors.initials: S
authors.lastname: Ong
authors.forename: Dieu H
authors.initials: DH
authors.lastname: Lao
authors.forename: Yevgeniya E
authors.initials: YE
authors.lastname: Koshman
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Allen M
authors.initials: AM
authors.lastname: Samarel
authors.forename: David R
authors.initials: DR
authors.lastname: Critchley
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
mesh_terms: D000328:Adult; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D016608:Talin / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C518832:TLN1 protein, human; C436513:TLN2 protein, human; C518833:TLN2 protein, mouse; D016608:Talin; C496077:Tln1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3