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

Abstract

Abstract Background At present, there is no official approved drug for improving muscle endurance. Our previous research found that acute phase protein Orosomucoid was an endogenous anti-fatigue protein, elevated by erythromycin to promote muscle bioenergetics and endurance. Here, we try to find a non-antibiotic erythromycin derivative improving muscle endurance. Methods The antibacterial activity was evaluated by bacterial inhibition ring test and 16S rRNA sequencing of the feces. Mice muscle endurance was evaluated by forced-swimming and treadmill-running. Fatigue index of isolated soleus muscle was evaluated by electrically evoked contraction. Glycogen content and mitochondrial number were tested by glycogen assay kit and transmission electron microscope. The expression of Orosomucoid in tissues and cells was detected by western blotting. Orosomucoid-targeting activity of HMS-01 was evaluated on Orosomucoid-deficient mice. Results HMS-01 is a novel erythromycin derivative, which lost antibacterial activity and could time- and dose-dependently prolong mice force-swimming and running time, improving fatigue index of soleus muscle. Moreover, HMS-01 increased glycogen content and mitochondria numbers in liver and muscle, and Orosomucoid level in vivo and in vitro. In Orosomucoid-deficient mice, the anti-fatigue and glycogen-elevation activity of HMS-01 disappeared. Conclusions HMS-01 may be a promising small molecule drug targeting Orosomucoid to enhance muscle endurance.