Deletion of cytosolic phospholipase A2 promotes striated muscle growth

Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A(2) (PLA(2)) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA(2) 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 PLA(2). The mechanism underlying this phenotype is that cytosolic PLA(2) negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA(2) 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 PLA(2) and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.