A non‐antibiotic erythromycin derivative improves muscle endurance by regulating endogenous anti‐fatigue protein orosomucoid in mice

Abstract At present, there are no official approved drugs for improving muscle endurance. Our previous research found acute phase protein orosomucoid (ORM) is an endogenous anti‐fatigue protein, and macrolides antibiotics erythromycin can elevate ORM level to increase muscle bioenergetics and endurance parameters. Here, we further designed, synthesized and screened a new erythromycin derivative named HMS‐01, which lost its antibacterial activity in vitro and in vivo. Data showed that HMS‐01 could time‐ and dose‐dependently prolong mice forced‐swimming time and running time, and improve fatigue index in isolated soleus muscle. Moreover, HMS‐01 treatment could increase the glycogen content, mitochondria number and function in liver and skeletal muscle, as well as ORM level in these tissues and sera. In Orm ‐deficient mice, the anti‐fatigue and glycogen‐elevation activity of HMS‐01 disappeared. Therefore, HMS‐01 might act as a promising small molecule drug targeting ORM to enhance muscle endurance.