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The muscle stem cell niche is well-described as influencing myogenic cell fate decision; however, the intrinsic mechanisms driving muscle stem cell progression during myogenesis are not yet fully elucidated. Here, we demonstrate that bioactive lipid class switching, an auto-regulatory mechanism originally described during the inflammatory process, is conserved during myogenesis. During the transition from proliferation to differentiation, myogenic cells shift from pro-inflammatory to pro-resolution pathways, a process partially mediated by 15Δ-PGJ2 that promotes the expression of the prostaglandin inactivation enzyme 15-hydroxyprostaglandin dehydrogenase. Using pharmacological inhibitors and knockout models of the pro-resolution enzyme 15-lipoxygenase, we show that blocking the bioactive lipid class switching impairs myoblast differentiation in vitro and muscle regeneration in vivo. Administration of the pro-resolving mediator Protectin-D1 restores myogenesis, enhances muscle regeneration post-injury and improves muscle phenotype in a dystrophic mouse model. Overall, these findings provide a better comprehension of the mechanisms regulating myogenic progression, which opens new therapeutic avenues for muscle regeneration and dystrophies. Here they show that myogenic cells shift their bioactive lipid profile from pro-inflammatory to pro-resolving during myogenesis. Disrupting this transition impairs differentiation, whereas Protectin-D1 restores fusion and improves muscle phenotype in a dystrophic model.
Fabre et al. (Tue,) studied this question.