Deletion of cytosolic phospholipase A2 promotes striated muscle growth

• Published in: Nature medicine Vol. 9; no. 7; pp. 944 - 951
• Main Authors: Haq, Syed, Kilter, Heiko, Michael, Ashour, Tao, Jingzang, O'Leary, Eileen, Sun, Xio Ming, Walters, Brian, Bhattacharya, Kausik, Chen, Xin, Cui, Lei, Andreucci, Michele, Rosenzweig, Anthony, Guerrero, J Luis, Patten, Richard, Liao, Ronglih, Molkentin, Jeffery, Picard, Michael, Bonventre, Joseph V, Force, Thomas
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.07.2003
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Animals; Arachidonic Acid - metabolism; Cardiomegaly - genetics; Cardiomegaly - pathology; Cells, Cultured; Cytosol - enzymology; Female; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I - metabolism; Mice; Mice, Mutant Strains; Muscle, Skeletal - growth & development; Muscle, Skeletal - metabolism; Organ Size - genetics; Phospholipases A - genetics; Phospholipases A - metabolism; Phospholipases A2; Phosphoproteins - metabolism; Protein Kinase C - metabolism; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm891

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.