Hypoglycemic drug liraglutide alleviates low muscle mass by inhibiting the expression of MuRF1 and MAFbx in diabetic muscle atrophy

Background: Low muscle mass, i.e. muscular atrophy, is an independent risk factor for type 2 diabetes mellitus (T2DM). Few studies investigated whether hypoglycemic drugs can alleviate low muscle mass and related mechanisms. Methods: This study recruited 51 type-2 diabetes mellitus (T2DM) patients, who were divided into two groups based on skeletal muscle index (SMI) evaluated by Dual-energy X-ray absorptiometry (DXA): the experiment group (n=25, SMI<7 kg/m 2 ) and the control group (n=26, SMI≥7 kg/m 2 ). GLP-1 levels were measured by EILSA. In vitro, 10 KK-A y mice (11-12-week-old) were assigned into two groups: liraglutide group (n=5) and saline group (n=5). Real-time PCR and Western blot were used to determine the expression levels of muscle specific ubiquitin protease E3, MuRF1 and MAFbx. Results: T2DM patients with a higher SMI had significantly higher GLP-1 levels (t=3.77, p <0.001). SMI were positively associated with GLP-1 levels (β=0.435, p =0.001) and inversely associated with age (β=0.299, p =0.015). The incidence of low muscle mass at below the second quartiles was 10.55 times that of above the second quartiles (odds ratio=10.556, p <0.001). Liraglutide-treatment mice showed significant decrease in food intake, final body weight, fasting blood glucose and significant increase in skeletal muscle mass, which coincided with the significant decrease in the expression levels of ubiquitin protease E3 MuRF1 and MAFbx. In vitro studies showed that liraglutide promoted myogenic differentiation and attenuated dexamethasone (DEX)-induced myotube atrophy. Ectopic expression of MuRF1 and MAFbx antagonized the beneficial effects of liraglutide on DEX-induced myotube atrophy. Conclusion: T2DM patients have muscular atrophy, and liraglutide alleviates muscular atrophy at least in part by inhibiting the expression of MuRF1 and MAFbx.