A Translational Investigation into Palmitoylethanolamide in Skeletal Muscle Repair

Palmitoylethanolamide (PEA), an endogenous fatty acid amide with analgesic and antiinflammatory properties, has recently emerged as a potential alternative to non-steroidal anti-inflammatory drugs (NSAIDs) for the management of exercise-induced muscle damage (EIMD). Widespread reliance on NSAIDs among athletes, combined with growing concerns surrounding their efficacy and long-term safety, has underscored the need for safer strategies. This thesis aimed to investigate PEA from four distinct, yet interrelated perspectives: (i) the prevalence and perceptions of NSAID use among endurance athletes, to evaluate usage behaviours and attitudes towards potential alternatives, (ii) the mechanistic influence of PEA on skeletal muscle in vitro, (iii) its comparative effects with ibuprofen on protein metabolism in vitro, and (iv) it’s potential to alleviate symptoms of EIMD in vivo. A survey of ultra-endurance runners first established the high prevalence of NSAID consumption and highlighted an openness to consider safer alternatives. In vitro investigations using C2C12 skeletal muscle cells demonstrated that PEA supported myogenic differentiation while modulating transcriptional pathways involved in inflammation. These findings were extended through dynamic proteomic analyses comparing PEA and ibuprofen, which revealed that both compounds stimulated ribosomal biogenesis, with PEA uniquely increasing synthesis of proteins associated with the small ribosomal subunit. Finally, a randomised, placebo-controlled trial examined the effects of PEA supplementation compared to ibuprofen and placebo in alleviating EIMD symptoms using a muscle-damaging downhill running protocol. Although no significant group differences were observed in muscle function or renal outcomes, both PEA and ibuprofen were associated with an earlier reduction in muscle pain perception. Taken together, these findings provide novel insights into the actions of PEA on skeletal muscle at both the gene and protein level, while offering preliminary evidence of its potential role in mitigating EIMD-related pain. This thesis contributes important context to the emerging conversation on alternatives to NSAID use in sport and exercise and provides a foundation for future research into the therapeutic potential of PEA.