Quercetin and Kaempferol Mitigate Endotoxin‐Induced Skeletal Muscle Wasting by Inhibiting KLF15 Expression and Restoring the Antioxidant System

The loss of muscle mass or muscle atrophy is a significant health concern associated with aging, diabetes, cardiovascular diseases, environmental toxicity, and inflammation, and it is becoming a significant issue requiring effective therapeutic strategies. Sepsis is caused by bacterial infection leading to inflammation and has a plethora of consequences, one of which is loss of muscle mass commonly observed for intensive care unit patients with a high morbidity rate. Flavonoids are well-known natural compounds for restoring muscle wasting. Our study investigates the efficacy of two flavonoids, quercetin and kaempferol, in mitigating lipopolysaccharide (LPS)-induced muscle atrophy. LPS treatment was followed by increased ROS production, upregulated inflammation (NF-Kβ, TLR4, MyD88, IL-6), and disruption of mitochondrial homeostasis in C2C12 myoblasts. The KLF15 knockdown cellular model also revealed a negligible effect of LPS in C2C12. Furthermore, the antioxidant properties of quercetin and kaempferol, individually and in combination, were evidenced to attenuate LPS-induced cellular oxidative stress and promote myogenesis by downregulating inflammatory regulators and atrophy-related genes triggered by LPS. Hence, this study illuminates the status of quercetin's and kaempferol's cytoprotective effect, individually and in combination, on muscle cells affected by sepsis-induced atrophy.