Ursolic acid attenuates sarcopenia through IL-17a-related gut-muscle axis in senile diabetic mice and myotube model

Abstract

Sarcopenia significantly impairs quality of life, especially in diabetic patients, where effective treatment options remain limited. The IL-17a-related gut-muscle axis suggests a potential role of the gut microbiota in the development of sarcopenia. Ursolic acid (UA) has shown promise as an anti-sarcopenic agent. Nevertheless, the relationship between UA and the IL-17a-related gut-muscle axis remains unclear. In this research, sarcopenia model was established using streptozotocin in vivo and in vitro with TNF-α-managed C2C12 myotubes. UA significantly altered the gut microbiota, notably increasing observed OTUs and the Shannon index of sarcopenic mice. Specifically, UA effectively mitigated the decrease of Bacteroides thetaiotaomicron and restored the total level of short-chain fatty acids, particularly reducing propionic acid and increasing isovaleric acid. Additionally, UA markedly improved muscle quality and function, as evidenced by increased body weight, grip strength, and muscle weight, as well as significantly decreased expression of Atrogin-1 and MuRF-1. Moreover, RNA sequencing results clearly indicated that UA suppressed the IL-17 signaling pathway in sarcopenic mice. Furthermore, UA alleviated oxidative stress and apoptosis in sarcopenic mice. Notably, UA inhibited the IL-17a pathway in sarcopenic mice by suppressing the heightened expression of the proteins. In vitro experiments further confirmed that UA inhibited TNF-α-induced myotube atrophy, reduced Atrogin-1 and MuRF-1 expression, and strongly suggested that IL-17a may be a key target of UA in combating myotube atrophy. The study emphasizes the importance of UA in alleviating sarcopenia, possibly through the IL-17a-related gut-muscle axis.