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Broiler skeletal muscle dysplasia is characterized by impaired muscle fiber hypertrophy and satellite cell dysfunction, leading to reduced meat yield and increased feed conversion rates, resulting in significant economic losses. With the impending global ban on β-adrenergic agonists, developing effective natural alternative treatments is an urgent requirement. Urolithin A (UA), a tannic acid metabolite derived from the gut microbiota, promotes muscle synthetic metabolism in mammals; however, its underlying mechanism in poultry remains unclear. We integrated network pharmacology, molecular docking, molecular dynamics simulations, and primary chicken skeletal muscle satellite cell (SMSC) culture experiments. A network pharmacology analysis identified threonine kinase1 (Akt1) as a key core target regulated by UA in muscle dysplasia. Further, KEGG enrichment analysis revealed differential clustering in the phosphatidylinositol-3-kinase (PI3K)-Akt1, forkhead box protein O1, and mechanistic target of rapamycin complex 1 signaling pathways. Molecular docking revealed that UA stably binds to the Akt1 protein (Binding energy: -7.7 kcal/mol), stabilized by hydrophobic interactions with Val164 and Met281. The key binding site for UA exhibits high conservation (96% homology) between mammalian and avian species. The 100 ns molecular dynamics simulation confirmed the stability of the complex. These findings indicate that the Akt1 pathway is closely associated with the protective role of uric acid in broiler muscle dysplasia. Primary skeletal muscle satellite cell experiments demonstrated that during SMSC proliferation, 50 μM UA upregulates mRNA levels of Akt1, mTORC1, and forkhead box O1, while enhancing the expression of myogenic differentiation 1 and myogenin during both proliferation and differentiation (P < 0.05). In addition, Akt1 and phosphorylated Akt1 protein levels upregulated (P < 0.05), confirming pathway activation. 50 μM UA regulates glucose metabolism by upregulating (P < 0.05) and downregulating (P < 0.05) pyruvate dehydrogenase kinase 4 (proliferation/differentiation) mRNA levels and fructose-6-phosphate kinase/fructose-2,6-bisphosphatase 3 (differentiation) mRNA levels, respectively, thereby optimizing glycolysis-oxidation balance. Our research shows that UA influences skeletal muscle satellite cells proliferation and differentiation through the Akt1 pathway and alters glucose metabolism at different stages. As a natural, residue-free compound, it holds promise for enhancing skeletal muscle growth in broilers, supporting the shift towards antibiotic-free poultry. Further animal studies are needed to confirm these in vitro results.
Wu et al. (Fri,) studied this question.