P‐Coumaric Acid Improves Skeletal Muscle Atrophy in Chronic Kidney Disease by Modulating TLR4/MyD88/NF‐κB‐Mediated Inflammation and Oxidative Stress

ABSTRACT Skeletal muscle atrophy is a prevalent complication in chronic kidney disease (CKD), and its pathogenesis is closely related to inflammation and oxidative stress. P‐Coumaric acid (PCA) is a phenolic acid with anti‐inflammatory and antioxidant pharmacological actions. This research aims to investigate the effect of PCA on CKD‐induced muscle atrophy and its underlying mechanism. In our study, in vivo and in vitro models were established by using 5/6 nephrectomized rats and LPS‐induced C2C12 myoblasts. The experimental results showed that PCA ameliorated kidney injury in CKD rats and increased skeletal muscle weight and the cross‐sectional area of muscle fibres. In both CKD rats and LPS‐induced C2C12 myoblasts, PCA also exhibited anti‐inflammatory and antioxidant effects, reduced the levels of pro‐inflammatory cytokines and enhanced the activity of antioxidant enzymes. Network pharmacology studies have identified 165 common targets between PCA and skeletal muscle atrophy. Furthermore, the experimental results also demonstrated that PCA decreased the expression of TLR4, MyD88, NF‐κB p65, MurF1 and MAFbx at both the protein and mRNA levels. Additionally, in vitro experiments showed that the use of TLR4 agonists could reverse the muscle‐protective effect of PCA. In summary, this study illustrated that PCA ameliorated skeletal muscle atrophy in CKD rats by inhibiting the TLR4/MyD88/NF‐κB pathway.