title: Extracellular matrix downregulation in the Drosophila heart preserves contractile function and improves lifespan.
abstract: Aging is associated with extensive remodeling of the heart, including basement membrane (BM) components that surround cardiomyocytes. Remodeling is thought to impair cardiac mechanotransduction, but the contribution of specific BM components to age-related lateral communication between cardiomyocytes is unclear. Using a genetically tractable, rapidly aging model with sufficient cardiac genetic homology and morphology, e.g. Drosophila melanogaster, we observed differential regulation of BM collagens between laboratory strains, correlating with changes in muscle physiology leading to cardiac dysfunction. Therefore, we sought to understand the extent to which BM proteins modulate contractile function during aging. Cardiac-restricted knockdown of ECM genes Pericardin, Laminin A, and Viking in Drosophila prevented age-associated heart tube restriction and increased contractility, even under viscous load. Most notably, reduction of Laminin A expression correlated with an overall preservation of contractile velocity with age and extension of organismal lifespan. Global heterozygous knockdown confirmed these data, which provides new evidence of a direct link between BM homeostasis, contractility, and maintenance of lifespan.
authors: Biomedical Sciences Program, UC, San Diego; La Jolla, CA 92093, USA.
authors: Ayla O
authors: AO
authors: Sessions
authors: Department of Bioengineering, UC, San Diego; La Jolla, CA 92093, USA.
authors: Gaurav
authors: G
authors: Kaushik
authors: Advanced Clinical Biosystems Research Institute; Barbra Streisand Women's Heart Center; Cedars-Sinai Heart Institute; Cedars-Sinai Medical Center; Los Angeles, CA 90048, USA.
authors: Sarah
authors: S
authors: Parker
authors: Advanced Clinical Biosystems Research Institute; Barbra Streisand Women's Heart Center; Cedars-Sinai Heart Institute; Cedars-Sinai Medical Center; Los Angeles, CA 90048, USA.
authors: Koen
authors: K
authors: Raedschelders
authors: Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute; La Jolla, CA 92037, USA.
authors: Rolf
authors: R
authors: Bodmer
authors: Advanced Clinical Biosystems Research Institute; Barbra Streisand Women's Heart Center; Cedars-Sinai Heart Institute; Cedars-Sinai Medical Center; Los Angeles, CA 90048, USA.
authors: Jennifer E
authors: JE
authors: Van Eyk
authors: Biomedical Sciences Program, UC, San Diego; La Jolla, CA 92093, USA; Department of Bioengineering, UC, San Diego; La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: aengler@ucsd.edu.
authors: Adam J
authors: AJ
authors: Engler
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster; D005109:Extracellular Matrix / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007797:Laminin / Q000235:genetics; D040542:Mechanotransduction, Cellular; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D029721:Drosophila Proteins; D007797:Laminin; C585456:Prc protein, Drosophila; C084098:laminin A; D003094:Collagen
keywords: Aging; Basement membrane; Drosophila; Extracellular matrix; Laminin A