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Deletion of cytosolic phospholipase A2 promotes striated muscle growth

Nature Medicine volume 9, pages 944–951 (2003)Cite this article

An Erratum to this article was published on 01 September 2003

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.

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Figure 1: Phenotype of the Pla2g4a−/− mouse.
Figure 2: Regulation of IGF-1 signaling by cytosolic PLA2.
Figure 6: Profile of IGF-1 signaling in Pla2g4a−/− mouse striated muscle.
Figure 3: Regulation of IGF-1R and IRS-1 in Pla2g4a−/− cells.
Figure 4: Regulation of IGF-1 signaling by PKC-ζ.
Figure 5: Regulation of PKC-ζ by arachidonic acid.

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References

  1. Balsinde, J. & Dennis, E.A. Function and inhibition of intracellular calcium-dependent phospholipase A2 . J. Biol. Chem. 272, 16069–16072 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Leslie, C.C. Properties and regulation of cytosolic phospholipase A2 . J. Biol. Chem. 272, 16709–16712 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Bonventre, J.V. et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2 . Nature 390, 622–625 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Uozumi, N. et al. Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390, 618–622 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Takaku, K. et al. Suppression of intestinal polyposis in Apc(Δ716) knockout mice by an additional mutation in the cytosolic phospholipase A2 gene. J. Biol. Chem. 275, 34013–34016 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Hong, K.H., Bonventre, J.C., O'Leary, E.O., Bonventre, J.V. & Lander, E.S. Deletion of cytosolic phospholipase A2 suppresses Apcmin-induced tumorigenesis. Proc. Nat. Acad. Sci. USA. 98, 3935–3939 (2000).

    Article  Google Scholar 

  7. Kunapuli, P., Lawson, J.A., Rokach, J.A., Meinkoth, J.L. & Fitzgerald, G.A. Prostaglandin F2α and the isoprostane, 8,12-iso-Isoprostane F2α-III, induce cardiomyocyte hypertrophy. J. Biol. Chem. 273, 22442–22452 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Lai, J. et al. Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vivo. Am. J. Physiol. 271, H2197–H2208 (1996).

    CAS  PubMed  Google Scholar 

  9. Shima, H. et al. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J. 17, 6649–6659 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shioi, T. et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19, 2537–2548 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Weinkove, D. & Leevers, S.J. The genetic control of organ growth: insights from Drosophila. Curr. Opin. Genet. Dev. 10, 75–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Haq, S. et al. Glycogen synthase kinase-3β is a negative regulator of cardiomyocyte hypertrophy. J. Cell. Biol. 151, 117–129 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Crackower, M.A. et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737–749 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Lupu, F., Terwilliger, J.D., Lee, K., Segre, G.V. & Efstratiadis, A. Roles of growth hormone and IGF-1 in mouse postnatal growth. Dev. Biol. 229, 141–162 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Cittadini, A. et al. Importance of an intact growth hormone/IGF-1 axis for normal post-infarction healing: studies in dwarf rats. Endocrinology 142, 332–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Haq, S. et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 103, 670–677 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Fazio, S., Palmieri, E.A., Biondi, B. & Sacca, L. The role of the GH-IGF-1 axis in the regulation of myocardial growth: from experimental models to human evidence. Eur. J. Endocrinol. 142, 211–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Duerr, R.L. et al. IGF-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J. Clin. Invest. 95, 619–627 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Musaro, A., McCullagh, K.J.A., Naya, F.J., Olson, E.N. & Rosenthal, N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400, 581–585 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Musaro, A. et al. Localized IGF-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat. Genet. 27, 195–200 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Pete, G. et al. Postnatal growth responses to insulin-like growth factor I in insulin receptor substrate-1-deficient mice. Endocrinology 140, 5478–5487 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Wang, J., Zhou, J., Powell-Braxton, L. & Bondy, C. Effects of Igf1 gene deletion on postnatal growth patterns. Endocrinology 140, 3391–3394 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Welch, S. et al. Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ. Res. 90, 641–648 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Sheridan, A.M. et al. PLIP, a novel splice variant of TIP60, interacts with Group IV cytosolic phospholipase A2, induces apoptosis and potentiates prostaglandin production. Mol. Cell. Biol. 14, 4470–4481 (2001).

    Article  Google Scholar 

  25. Ravichandran, L.V., Esposito, D.L., Chen, J. & Quon, M.J. Protein kinase C ζ phosphorylates insulin receptor substrate-1 and impairs its ability to activate PI3-K in response to insulin. J. Biol. Chem. 276, 3543–3549 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. LeGood, J.A. et al. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281, 2042–2045 (1998).

    Article  CAS  Google Scholar 

  27. Balendran, A., Hare, G.R., Kieloch, A., Williams, M.R. & Alessi, D.R. Further evidence that PDK1 is required for the stability and phosphorylation or protein kinase C (PKC) isoforms. FEBS Lett. 484, 217–223 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Williams, M.R. et al. The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr. Biol. 10, 439–448 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Chou, M.M. et al. Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr. Biol. 19, 1069–1077 (1998).

    Article  Google Scholar 

  30. Donohue, T.J. et al. Induction of myocardial IGF-1 gene expression in left ventricular hypertrophy. Circulation 89, 799–809 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Belke, D.D. et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J. Clin. Invest. 109, 629–639 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shiojima, I. et al. Akt signaling mediates postnatal heart growth in response to insulin and nutritional status. J. Biol. Chem. 277, 37670–37677 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Bueno, O.F. et al. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 19, 6341–6350 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fernandez, A.M. et al. Muscle-specific inactivation of the IGF-1 receptor induces compensatory hyperplasia in skeletal muscle. J. Clin. Invest. 109, 347–355 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shioi, T. et al. Akt/Protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22, 2799–2809 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rui, L. et al. Insulin/IGF-1 and TNFα stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J. Clin. Invest. 107, 181–189 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu, Y.F. et al. Insulin stimulates PKC-ζ -mediated phosphorylation of IRS-1. J. Biol. Chem. 276, 14459–14465 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Eldar-Finkelman, H. & Krebs, E.G. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc. Nat. Acad. Sci. USA 94, 9660–9664 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. VanHaesebroeck, B. & Alessi, D.R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 346, 561–576 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang, J. et al. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell 9, 1227–1240 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Balendran, A. et al. A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase C ζ and PKC-related kinase 2 by PDK1. J. Biol. Chem. 275, 20806–20813 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Van der Hoeven, P.C.J., van der Wal, J.C.M., Ruurs, P. & van Blitterswijk, W.J. Protein kinase C activation by acidic proteins including 14-3-3. Biochem J. 347, 781–785 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. He, T.C. et al. A simplified system for generating recombinant adenoviruses. Proc. Nat. Acad. Sci. USA 95, 2509–2514 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Choukroun, G. et al. Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases. J. Clin. Invest. 104, 391–398 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goruppi, S., Bonventre, J.V., & Kyriakis, J.M. Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertrophy. EMBO J. 21, 5427–5436 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank C. Serhan, A. Sapirstein, G. Choukroun and W. Han for their invaluable advice. This work was supported by the Peel Medical Research Trust, an American Heart Association Scientist Development Grant, the Wellcome Trust (S.H.), Associazione Leonardo Di Capua (M.A.), grants from the National Institutes of Health (DK50282, HL61688 and HL67371) and an Established Investigator Award of the American Heart Association. This article is dedicated to Fazilatun Nessa Haq and to the memory of the late Sayyid Azizul Haq, M.B., B.S.

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Author notes

  1. Michele Andreucci

    Present address: Ricercatore at Magna Graecia University, Catanzaro, I-88100, Italy

  2. Syed Haq, Heiko Kilter and Ashour Michael: These authors contributed equally to this work.

Authors and Affiliations

  1. Tufts-New England Medical Center and Department of Medicine, Molecular Cardiology Research Institute, Tufts University School of Medicine, Boston, 02111, Massachusetts, USA

    Syed Haq, Heiko Kilter, Ashour Michael, Brian Walters, Kausik Bhattacharya, Xin Chen, Richard Patten & Thomas Force

  2. Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Jingzang Tao, Eileen O'Leary, Xio Ming Sun, Michele Andreucci, Anthony Rosenzweig, J. Luis Guerrero & Michael Picard

  3. Boston University Medical Center and School of Medicine, Boston, 02118, Massachusetts, USA

    Lei Cui & Ronglih Liao

  4. Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, 45229, Ohio, USA

    Jeffery Molkentin

  5. Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Joseph V. Bonventre

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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

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