Palmitoylethanolamide supplementation partly modulates eccentric exercise-induced changes in the bioactive lipid profile of skeletal muscle tissue.

Strenuous exercise induces microstructural muscle damage, leading to delayed onset muscle soreness and reduced performance. Although structural changes are well documented, subsequent inflammatory responses are not fully understood. Research has mainly examined leukocyte infiltration and cytokine expression, while low-abundance bioactive lipid mediators remain understudied. Nutritional strategies, such as palmitoylethanolamide (PEA) supplementation, can modulate these mediators and promote anti-inflammatory, pro-resolving conditions, which may improve recovery. Therefore, the present study evaluated the effect of PEA on the abundance of bioactive lipid mediators in skeletal muscle tissue of healthy males following muscle damaging exercise (MDE). 10 participants were included in a double-blind crossover study where they received PEA (2 × 350 mg/d, Levagen+) or placebo (PLA, maltodextrin), in a randomized order. In each experimental condition participants performed an MDE bout (24 × 10 eccentric contractions of the knee extensors on an isokinetic dynamometer). Muscle biopsies were collected at baseline and 48 h following MDE and analysed for lipid mediator profile via LC-MS/MS-based lipidomics. Many lipid mediators decreased 48 h post-exercise in PLA, whereas they remained unchanged or increased in PEA. This pattern was observed for mediators derived from AA (12-HHTrE, 11-HETE, 12-HETE, 15-HETE, 15-epi-LXA4, 14,15-EpETrE, 5,6-DiHETrE), DHA (4-HDoHE), LA (9-HODE, 13-HODE) and ALA (9-HOTrE, 13-HOTrE). MCTR3 levels were consistently higher in PEA compared to PLA, whereas concentrations of LXB4 and AT-RvD3 were consistently lower in PEA compared to PLA, independent of exercise. In conclusion, PEA supplementation attenuated or counteracted the decline in lipid mediators following exercise, indicating that PEA partially enhances bioactive lipid tone in response to strenuous exercise.