Metabolomic and transcriptomic effects of melatonin and gut microbiota through microbes and exosomes on muscle regeneration and enhancement of sports performance: a systematic review

Introduction: Sleep and recovery are essential for optimizing exercise performance. However, the effectiveness of melatonin supplementation in improving sleep quality and next-day physical performance remains uncertain. Research has demonstrated the ergogenic effect of melatonin (N-acetyl-5-methoxytryptamine) (MEL) in increasing exhaustive aerobic activity. Associated with the effects of MEL, adult tissue stem cells (mesenchymal stem cells) mediate homeostasis and regeneration of tissues and organs, integrating signaling cues and metabolic inputs with the release of exosomes and microRNAs to enhance athletic performance. Objective: It was demonstrated through a systematic review study the regulation of melatonin and gut microbiota by cellular and molecular metabolic pathways, such as microRNAs and exosomes, in the process of muscle regeneration and increased sports performance. Methods: The PRISMA Platform systematic review rules were followed. The research was carried out from July to August 2025 in the Scopus, Embase, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 136 articles were found, and 55 articles were evaluated in full and 29 were included and developed in the present systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 25 studies with a high risk of bias and 12 studies that did not meet GRADE and AMSTAR-2. Most studies showed homogeneity in their results, with X2=82.9%>50%. It was concluded that administering 6 mg of melatonin at night improved performance during high-intensity exercise the following day and enhanced perceived recovery up to 72 hours after exercise. Melatonin intake during training has beneficial effects on physical performance and protects tissues against the deleterious effects of reactive oxygen species and cellular damage. Furthermore, nocturnal melatonin supplementation during an athlete's intense training session alleviated oxidative stress, leukocytosis, and cellular damage, and improved performance recovery. Melatonin plays important roles in regulating the regenerative activities of mesenchymal stem cells, which, along with nutrients, modulate the activities of exosomes and microRNAs in the muscle regeneration process.