The polyphenol metabolite urolithin A suppresses myostatin expression and augments glucose uptake in human skeletal muscle cells

PURPOSE: Polyphenolic plant extracts have demonstrated anti-inflammatory and anti-catabolic effects in vitro, however their meaningful translation into humans remains elusive. Urolithin A (UA), a gut-derived metabolite of ellagitannins, has shown promise for improving muscle function and metabolic health in rodent models. This study aimed to explore the impact of UA on insulin and anabolic sensitivity in human skeletal muscle cells. METHODS: Primary human myogenic cultures were derived from skeletal muscle biopsies of eight healthy adults. After differentiation, myotubes were treated with 0.002, 1 and 50 µM UA or vehicle for 24 h. Cell viability was assessed using a resazurin assay. Basal and insulin-stimulated glucose uptake was measured using tritiated deoxy-D-glucose, whilst amino acid-stimulated protein synthesis was estimated using the surface sensing of translation (SuNSET) technique. Expression of myostatin and glucose transporters was quantified via real-time PCR. RESULTS: UA treatment at ≤ 50 µM did not compromise cell viability. Treatment with 50 µM UA enhanced both basal- and insulin-stimulated glucose uptake by 21% (P < 0.05) and 24% (P < 0.01), respectively, compared to vehicle and was accompanied by a 1.8-fold upregulation of GLUT4 expression (P < 0.01). 50 µM UA reduced myostatin (MSTN) expression by 14% (P < 0.01) but did not alter amino acid-stimulated global cell protein synthesis. CONCLUSION: This study provides evidence of UA's metabolic benefits in primary human myotubes, notably improving basal- and insulin-stimulated glucose uptake and supressing MSTN expression. These findings suggest UA could be an effective nutraceutical for mitigating insulin resistance and warrants further investigation.