title: Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis.
abstract: AMP-activated protein kinase (AMPK) is a metabolic enzyme that can be activated by nutrient stress or genetic mutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, and ventricular pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show that activating PRKAG2 mutations increase microtissue twitch force by enhancing myocyte survival. Integrating RNA sequencing with metabolomics, PRKAG2 mutations that activate AMPK remodeled global metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism instead of glycolysis. As in patients with PRKAG2 cardiomyopathy, iPS cell and mouse models are protected from cardiac fibrosis, and we define a crosstalk between AMPK and post-transcriptional regulation of TGFβ isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGFβ signaling.
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Cardiology Center, University of Connecticut Health, Farmington, CT 06030, USA. Electronic address: travis.hinson@jax.org.
authors.forename: J Travis
authors.initials: JT
authors.lastname: Hinson
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
authors.forename: Anant
authors.initials: A
authors.lastname: Chopra
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Lowe
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Calvin C
authors.initials: CC
authors.lastname: Sheng
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Rajat M
authors.initials: RM
authors.lastname: Gupta
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rajarajan
authors.initials: R
authors.lastname: Kuppusamy
authors.affiliation: Division of Cardiovascular Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: John
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Rowe
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Gorham
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Burke
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
authors.forename: Kehan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.affiliation: Division of Cardiovascular Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Cardiovascular Medicine, Beth Israel Deaconess Hospital, Boston, MA 02115, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wu
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: cseidman@genetics.med.harvard.edu.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation; D055442:Metabolome / Q000235:genetics; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D023822:Tissue Engineering / Q000379:methods; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1; D006003:Glycogen; C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; AMPK; PRKAG2; TGF-beta; Wolff-Parkinson-White syndrome; fibrosis; glycogen storage disease; hypertrophic cardiomyopathy