Author: ["Syed Haq","Heiko Kilter","Ashour Michael","Jingzang Tao","Eileen O'Leary","Xio Ming Sun","Brian Walters","Kausik Bhattacharya","Xin Chen","Lei Cui","Michele Andreucci","Anthony Rosenzweig","J. Luis Guerrero","Richard Patten","Ronglih Liao","Jeffery Molkentin","Michael Picard","Joseph V. Bonventre","Thomas Force"]
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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)-ζ, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-ζ, 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.Cite this article
Haq, S., Kilter, H., Michael, A. et al. Deletion of cytosolic phospholipase A2 promotes striated muscle growth. Nat Med 9, 944–951 (2003). https://doi.org/10.1038/nm891 