The Cellular and Molecular Mechanisms of Prostaglandin E₂ in Myogenesis

Prostaglandin E₂ (PGE₂), the most abundant prostaglandin (PG) in our body, has multiple biological functions related to physiological activities and the development of diseases. Emerging evidence has shown that PGE2 plays an important role in regulating the survival and proliferation of hematopoietic stem cells, suggesting that PGE₂ signaling could be essential for tissue development and regeneration. Previous results have also indicated that inhibition of PGE₂ synthesis through the cycoloxygenase-2 (COX-2) pathway at an early stage of muscle recovery from damage attenuated skeletal muscle regeneration. However, the exact mechanisms by which PGE₂ regulates skeletal muscle development and regeneration are elusive. In this project, the central hypothesis is that PGE₂ signaling through its G protein-coupled E prostanoid (EP) receptors is essential for skeletal muscle development or regeneration. Murine skeletal muscle cell line C2C12 was used as a model to test this hypothesis. The first part of the project is concerned with the role of PGE₂ in myogenic differentiation. Activation of PGE₂ signaling promoted C2C12 myogenic differentiation, which resulted from the upregulation of genes related to myogenic differentiation, calcium signaling and other pathways. Two EP receptors, EP1 and EP4, were identified as the major isoforms in C2C12 cells. Blockage of either receptor significantly inhibited C2C12 myogenesis. Our results indicated that EP1 signaling is involved in regulating myogenin expression, while activation of EP4 receptor is important for fusion. In addition, the effect of PGE₂ on myoblast proliferation was also determined. Although treatment with PGE₂ or EP1/4 agonist did not alter C2C12 proliferation, inhibition of either EP1 or EP4 receptor caused G0/G1 phase arrest, which subsequently inhibited C2C12 proliferation. Furthermore, COX-1 was shown to be the major COX isoform expressed in C2C12. Inhibition of COX-1, but not COX-2, negatively regulated C2C12 myogenic differentiation. In conclusion, our data have demonstrated that PGE₂ plays a multifaceted role in regulating C2C12 proliferation and myogenic differentiation through EP1 and EP4 receptors. Our results also provide new insights for the function of COX-1–derived PGE₂ during differentiation from myoblasts to myotubes.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Pharmacology and Toxicology (UMKC)

Grantor

University of Missouri--Kansas City

Year dc:date.issued

2013

Author dc:creator

• Mo, Chenglin

Advisor dc:contributor.advisor

• Igwe, Orisa John

Language dc:language.iso

en_US

Handle dc:identifier.uri

https://hdl.handle.net/10355/47462

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/47462