Nature Medicine
9, 944 - 951 (2003)
Published online: 15 June 2003; | doi:10.1038/nm891
There is an Erratum (September 2003) associated with this Article.
Deletion of cytosolic phospholipase A2 promotes striated muscle growthSyed Haq1, 7, Heiko Kilter1, 7, Ashour Michael1, 7, Jingzang Tao2, Eileen O'Leary2, Xio Ming Sun2, Brian Walters1, Kausik Bhattacharya1, Xin Chen1, Lei Cui3, Michele Andreucci2, 6, Anthony Rosenzweig2, J. Luis Guerrero2, Richard Patten1, Ronglih Liao3, Jeffery Molkentin4, Michael Picard2, Joseph V. Bonventre5
& Thomas Force11
Molecular Cardiology Research Institute, Tufts-New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. 2
Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129, USA. 3
Boston University Medical Center and School of Medicine, Boston, Massachusetts 02118, USA. 4
Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229, USA. 5
Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. 6
Present address: Ricercatore at Magna Graecia University, Catanzaro I-88100, Italy. 7
These authors contributed equally to this work.
Correspondence should be addressed to Syed Haq shaq@tufts-nemc.org or Thomas Force tforce@tufts-nemc.orgGeneration 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)- , a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-, 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.
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