Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):6675-6684. doi: 10.1073/pnas.1705420114. Epub 2017 Jun 12.

Abstract

Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.

Keywords: NSAIDs; PGE2; muscle stem cells; regeneration; strength.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dinoprostone / metabolism*
  • Mice
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / physiology*
  • Myoblasts, Skeletal / cytology
  • Myoblasts, Skeletal / metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism*
  • Regeneration / drug effects
  • Regeneration / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Nr4a2 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Ptger4 protein, mouse
  • Receptors, Prostaglandin E, EP4 Subtype
  • Cyclic AMP
  • Dinoprostone