title: A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging.
abstract: Cardiac performance decreases with age, which is a major risk factor for cardiovascular disease and mortality in the aging human population, but the molecular mechanisms underlying cardiac aging are still poorly understood. Investigating the role of integrin-linked kinase (ilk) and β1-integrin (myospheroid, mys) in Drosophila, which colocalize near cardiomyocyte contacts and Z-bands, we find that reduced ilk or mys function prevents the typical changes of cardiac aging seen in wildtype, such as arrhythmias. In particular, the characteristic increase in cardiac arrhythmias with age is prevented in ilk and mys heterozygous flies with nearly identical genetic background, and they live longer, in line with previous findings in Caenorhabditis elegans for ilk and in Drosophila for mys. Consistent with these findings, we observed elevated β1-integrin protein levels in old compared with young wild-type flies, and cardiac-specific overexpression of mys in young flies causes aging-like heart dysfunction. Moreover, moderate cardiac-specific knockdown of integrin-linked kinase (ILK)/integrin pathway-associated genes also prevented the decline in cardiac performance with age. In contrast, strong cardiac knockdown of ilk or ILK-associated genes can severely compromise cardiac integrity, including cardiomyocyte adhesion and overall heart function. These data suggest that ilk/mys function is necessary for establishing and maintaining normal heart structure and function, and appropriate fine-tuning of this pathway can retard the age-dependent decline in cardiac performance and extend lifespan. Thus, ILK/integrin-associated signaling emerges as an important and conserved genetic mechanism in longevity, and as a new means to improve age-dependent cardiac performance, in addition to its vital role in maintaining cardiac integrity.
authors.affiliation: Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Nishimura
authors.forename: Caroline
authors.initials: C
authors.lastname: Kumsta
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kaushik
authors.forename: Soda B
authors.initials: SB
authors.lastname: Diop
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.forename: Jumana
authors.initials: J
authors.lastname: Bisharat-Kernizan
authors.forename: Hannah
authors.initials: H
authors.lastname: Catan
authors.forename: Anthony
authors.initials: A
authors.lastname: Cammarato
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Engler
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.forename: Malene
authors.initials: M
authors.lastname: Hansen
authors.forename: Karen
authors.initials: K
authors.lastname: Ocorr
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000502:physiology; D004330:Drosophila; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
chemical_list: D019012:Integrin beta1; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK
keywords: Caenorhabditis elegans; Drosophila; arrhythmia; cardiomyopathy; cell adhesion; heart failure; ilk; myospheroid; parvin; paxillin; pinch; senescence; talin