Deletion of cytosolic phospholipase A2 promotes striated muscle growth |
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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 |
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Institution: | 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 |
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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. |
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