Deletion of cytosolic phospholipase A2 promotes striated muscle growth.
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.
Haq
Syed
S
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
Kilter
Heiko
H
Michael
Ashour
A
Tao
Jingzang
J
O'Leary
Eileen
E
Sun
Xio Ming
XM
Walters
Brian
B
Bhattacharya
Kausik
K
Chen
Xin
X
Cui
Lei
L
Andreucci
Michele
M
Rosenzweig
Anthony
A
Guerrero
J Luis
JL
Patten
Richard
R
Liao
Ronglih
R
Molkentin
Jeffery
J
Picard
Michael
M
Bonventre
Joseph V
JV
Force
Thomas
T
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology*; D005260:Female; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism*; D054467:Phospholipases A2; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D016718:Arachidonic Acid; D007334:Insulin-Like Growth Factor I; C081975:protein kinase C eta; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2