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

Abstract

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016.Contributed by Helen M. Blau, May 15, 2017 (sent for review April 3, 2017; reviewed by Douglas P. Millay and Fabio M. V. Rossi)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. muscle stem cells | PGE2 | regeneration | NSAIDs | strength

Adult stem cells and regenerative medicine—a symposium report

“…These effects were seen both when cells were treated with PGE2 ex vivo and transplanted into injured mice, and when MuSCs and PGE2 were coinjected into injured mice. PGE2 even improved endogenous MuSC activity when administered via intramuscular injection after muscle injury, suggesting that MuSC activity can be enhanced endogenously, without the need for stem cell transplant …”

“…EP4 is a receptor for prostaglandin E2 (PGE2), a proinflammatory lipid with a wide range of biological effects. Animal studies show that PGE2 is released by myofibers following muscle injury—a transient spike in PGE2 occurs approximately 3 days post injury …”

“…This translated to a decline in muscle strength following injury. In addition, blocking PGE2 production with nonsteroidal anti‐inflammatory drugs—common, over‐the‐counter painkillers—reduced MuSC activity and impaired muscle strength and regeneration following injury in mice …”

“…Animal studies show that PGE2 is released by myofibers following muscle injury-a transient spike in PGE2 occurs approximately 3 days post injury. 32 EP4/PGE2 signaling is required for MuSC function and regeneration. Impairing PGE2 signaling by conditional knockout of the EP4 gene (Prger4) in MuSCs impaired MuSC function, regeneration, and engraftment in mice.…”

Analgesic and anti‐inflammatory drugs in sports: Implications for exercise performance and training adaptations

“…Recent research suggests that these lipid metabolites can have direct regulatory effects on the skeletal muscle. For example, 12/15‐hydroxyeicosatetraenoic acids (HETEs) have been found to increase rates of protein breakdown in C2C12 myoblasts and myotubes, and several pro‐resolving lipid mediators play important roles in satellite cell differentiation and myogenesis . Interestingly, a recent study using LC‐MS‐based lipidomics revealed suppression of both early pro‐inflammatory and later anti‐inflammatory circulating lipid mediator responses in subjects orally receiving 400 mg ibuprofen .…”