title: Phosphoinositide 3-kinase (PI3K(p110alpha)) directly regulates key components of the Z-disc and cardiac structure.
abstract: Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110α) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110α) directly regulates components of the Z-disc and cardiac structure. To address this question, a unique three-dimensional virtual muscle model was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110α) activity under basal conditions (sham) and in a setting of myocardial infarction to display the location of structural proteins. Key findings from this analysis were then validated experimentally. The three-dimensional virtual muscle model visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere, including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110α) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110α) inhibitors and examining the myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland, 4111, Australia; Commonwealth Scientific and Industrial Research Organisation, Food Futures Flagship, Queensland Bioscience Precinct, St. Lucia, Queensland, 4067, Australia.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Waardenberg
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, 8008, Australia.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Dominic C H
authors.initials: DCH
authors.lastname: Ng
authors.affiliation: Department of Molecular Medicine, University of Auckland, Grafton, Auckland, 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Grafton, Auckland, 1142, New Zealand.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, 8008, Australia.
authors.forename: Nelly
authors.initials: N
authors.lastname: Cemerlang
authors.affiliation: Department of Genetics, Biology, and Biochemistry, University of Torino, Molecular Biotechnology Center, Torino, 10126, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Sbroggiò
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland, 4111, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Wells
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation, Food Futures Flagship, Queensland Bioscience Precinct, St. Lucia, Queensland, 4067, Australia.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Dalrymple
authors.affiliation: Department of Genetics, Biology, and Biochemistry, University of Torino, Molecular Biotechnology Center, Torino, 10126, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Brancaccio
authors.affiliation: Ramaciotti Centre for Gene Function Analysis and the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, 2052, Australia.
authors.forename: Ruby C Y
authors.initials: RCY
authors.lastname: Lin
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, 8008, Australia. Electronic address: julie.mcmullen@bakeridi.edu.au.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D054974:Costameres / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000378:metabolism; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal / Q000379:methods; D032342:Muscle Cells / Q000166:cytology; D009124:Muscle Proteins / Q000737:chemistry; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C122158:Itgb1bp2 protein, mouse; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase