Talin1 Has Unique Expression versus Talin 2 in the Heart and Modifies the Hypertrophic Response to Pressure Overload

• Published in: The Journal of biological chemistry 2013-02, Vol.288 (6), p.4252-4264
• Main Authors: Manso, Ana Maria, Li, Ruixia, Monkley, Susan J., Cruz, Nathalia M., Ong, Shannon, Lao, Dieu H., Koshman, Yevgeniya E., Gu, Yusu, Peterson, Kirk L., Chen, Ju, Abel, E. Dale, Samarel, Allen M., Critchley, David R., Ross, Robert S.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Cardiac Hypertrophy; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiomyopathy; Female; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Heart; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - pathology; Humans; Integrins; Male; MAP Kinase Signaling System - genetics; Mechanotransduction; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Bases of Disease; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Stress, Physiological - genetics; Talin; Talin - biosynthesis; Talin - genetics; Up-Regulation - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.427484

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. Background: Talin is an integrin-actin linker essential for integrin activation. Results: Talin1 has distinct developmental and postnatal expression in heart versus Talin2. Cardiac-myocyte specific Talin1 deletion alters physiological and molecular responses of the myocardium to stress. Conclusion: Talin1 has a unique mechanotransductive role in the cardiomyocyte. Significance: Reduction of talin1 in cardiomyocytes may have beneficial effects in the stressed myocardium.