title: Deletion of cytosolic phospholipase A2 promotes striated muscle growth.
abstract: Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a-/- mice, which lack the gene encoding cytosolic PLA2. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-zeta, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-zeta, correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.
authors.affiliation: Molecular Cardiology Research Institute, Tufts-New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. shaq@tufts-nemc.org
authors.forename: Syed
authors.initials: S
authors.lastname: Haq
authors.forename: Heiko
authors.initials: H
authors.lastname: Kilter
authors.forename: Ashour
authors.initials: A
authors.lastname: Michael
authors.forename: Jingzang
authors.initials: J
authors.lastname: Tao
authors.forename: Eileen
authors.initials: E
authors.lastname: O'Leary
authors.forename: Xio Ming
authors.initials: XM
authors.lastname: Sun
authors.forename: Brian
authors.initials: B
authors.lastname: Walters
authors.forename: Kausik
authors.initials: K
authors.lastname: Bhattacharya
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.forename: Michele
authors.initials: M
authors.lastname: Andreucci
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: J Luis
authors.initials: JL
authors.lastname: Guerrero
authors.forename: Richard
authors.initials: R
authors.lastname: Patten
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Jeffery
authors.initials: J
authors.lastname: Molkentin
authors.forename: Michael
authors.initials: M
authors.lastname: Picard
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology*; D005260:Female; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism*; D054467:Phospholipases A2; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D016718:Arachidonic Acid; D007334:Insulin-Like Growth Factor I; C081975:protein kinase C eta; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2