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

Ana Maria Manso; Ruixia Li; Susan J Monkley; Nathalia M Cruz; Shannon Ong; Dieu H Lao; Yevgeniya E Koshman; Yusu Gu; Kirk L Peterson; Ju Chen; E. Dale Abel; Allen M Samarel; David R Critchley; Robert S Ross

doi:10.1074/jbc.M112.427484

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

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

Ana Maria Manso, Ruixia Li, Susan J Monkley, Nathalia M Cruz, Shannon Ong, Dieu H Lao, Yevgeniya E Koshman, Yusu Gu, Kirk L Peterson, Ju Chen, …

The Journal of biological chemistry, Vol.288(6), pp.4252-4264

02/08/2013

DOI: 10.1074/jbc.M112.427484

PMCID: PMC3567677

PMID: 23266827

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Abstract

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. 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.

Heart

Cardiomyopathy

Molecular Bases of Disease

Talin

Mechanotransduction

Cardiac Hypertrophy

Integrins

Details

Title: Subtitle: Talin1 Has Unique Expression versus Talin 2 in the Heart and Modifies the Hypertrophic Response to Pressure Overload
Creators: Ana Maria Manso - From the
Ruixia Li
Susan J Monkley - the
Nathalia M Cruz - From the
Shannon Ong - From the
Dieu H Lao - UCSD School of Medicine, Department of Medicine, La Jolla, California 92093
Yevgeniya E Koshman - the
Yusu Gu - UCSD School of Medicine, Department of Medicine, La Jolla, California 92093
Kirk L Peterson - UCSD School of Medicine, Department of Medicine, La Jolla, California 92093
Ju Chen - UCSD School of Medicine, Department of Medicine, La Jolla, California 92093
E. Dale Abel - Division of Endocrinology, Metabolism, and Diabetes and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84108
Allen M Samarel - the
David R Critchley - the
Robert S Ross - From the
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(6), pp.4252-4264
DOI: 10.1074/jbc.M112.427484
PMID: 23266827
PMCID: PMC3567677
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: HL046345; HL103566 / National Institutes of Health
Alternative title: Talin1 and the Myocardium
Language: English
Date published: 02/08/2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024547602771

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