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

Clin Exp Pharmacol Physiol. 2024 Jul;51(7):e13873. doi: 10.1111/1440-1681.13873.

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.

Keywords: erythromycin derivatives; glycogen; mitochondria; muscle endurance; orosomucoid (ORM).

MeSH terms

  • Animals
  • Erythromycin* / analogs & derivatives
  • Erythromycin* / pharmacology
  • Glycogen* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fatigue* / drug effects
  • Muscle, Skeletal* / drug effects
  • Muscle, Skeletal* / metabolism
  • Orosomucoid* / metabolism
  • Physical Endurance* / drug effects

Substances

  • Erythromycin
  • Glycogen
  • Orosomucoid