Kukoamine B, a Lycium-Derived Polyamine Alkaloid, Attenuates High-Fat-Diet-Induced Skeletal Muscle Dysfunction with the Involvement of LPS/TLR4/NF-κB-Mediated Metabolic Inflammation.

A high-fat diet (HFD) promotes lipid metabolic disorders, chronic low-grade inflammation and skeletal muscle dysfunction. Kukoamine B (KB), a Lycium-derived polyamine alkaloid with reported anti-inflammatory and antioxidant activities, may protect against HFD-associated muscle impairment. C57BL/6J mice were fed an HFD and orally administered KB for 12 weeks. Muscle function was evaluated using inverted grid, forelimb grip strength and treadmill exhaustion tests. Histological, transcriptomic, ELISA, immunofluorescence and Western blot analyses were used to assess muscle injury and inflammatory signalling. KB reduced intramuscular lipid deposition, collagen accumulation and myofibre damage, improved muscle strength and exercise endurance, and partially restored AKT/mTOR-associated protein metabolic signalling. Transcriptomic analysis showed that KB downregulated HFD-activated inflammatory responses, chemokine signalling, lipopolysaccharide responses and Toll-like receptor-related pathways. KB also reduced plasma and skeletal muscle LPS levels, inhibited TLR4/MyD88/NF-κB signalling, and decreased TNF-α and IL-1β expression. TAK-242 mimicked the anti-inflammatory and muscle function-improving effects of KB, whereas their combination produced no statistically detectable additional effect under the conditions tested. These findings suggest that KB attenuates HFD-induced skeletal muscle dysfunction, potentially involving reduced LPS burden and suppression of TLR4/NF-κB-mediated metabolic inflammation.