Astragaloside ? Reverses Simvastatin-induced Skeletal Muscle Injury

Background:Statins,a kind of effective lipid-lowering drugs,which are widely used in the treatment of a variety of cardiovascular and cerebrovascular diseases.Since the statins came into the market in the1980s,it has been reported that long-term use of statins can cause skeletal muscle damage,mainly manifested as muscle pain,muscle weakness and rhabdomyolysis.Although statins can effectively prevent and treat cardiovascular and cerebrovascular diseases,the skeletal muscle damage caused by statins also seriously damages people's health.Therefore,it is an urgent research topic to explore a drug that can not affect the lipid-lowering effect of statins,but also eliminate or alleviate the damage of skeletal muscle caused by statins.Objective:Whether astragaloside can reverse the damage of simvastatin on skeletal muscle and explore its potential mechanism.Method:ApoE gene knockout(ApoE^-/-)mice were fed with high-fat diet for 4 weeks,and randomly divided into non exercise group,exercise group,exercise+simvastatin group,exercise+simvastatin+trimetazidine group,exercise+simvastatin+low dosage of astragaloside IV group,and exercise+simvastatin+high dosage of astragaloside IV group.At the end of the experiment,the strength of mice was tested by running endurance test,forepaw strength test and grid suspension test,and the morphology of gastrocnemius muscle was observed by H&E staining.The level of blood lipid was measured by measuring the total cholesterol,triglyceride,low density lipoprotein and free fatty acid in the serum of the mice.The gastrocnemius muscle of mice was stained by PAS,and the lactate level in serum was measured by biochemical kit to detect the energy metabolism of mice.The content of hydrogen peroxide,the level of mitochondrial membrane potential,the activity of mitochondrial complex?and citrate synthase were measured to evaluate the function and activity of mitochondria.Finally,Western blot and quantitative PCR were used to determine the expression level of related proteins and transcription factors.Result:ApoE gene knockout mice,high-fat diet 4 weeks,blood lipid significantly increased.when the mice administered simvastatin with certain intensity of exercise,simvastatin can accelerate the damage of skeletal muscle in mice,the main performance is that the sports endurance and claw force of mice are significantly reduced.H&E staining showed that the density of gastrocnemius muscle in the exercise+simvastatin group was significantly lower than that in the normal group.PAS staining also found that compared with the normal group,exercise+simvastatin group had more glycogen in gastrocnemius muscle.Compared with the normal group,the mitochondrial membrane potential,the activity of mitochondrial complex?and citrate synthase in gastrocnemius muscle of the exercise+simvastatin group decreased significantly.The above phenomenon was reversed to a great extent when astragaloside used.Further study on the mechanism of astragaloside showed that astragaloside can promote the phosphorylation of AMPK and activate PGC-1?,so as to up regulate the expression of Nrf1,which can act on downstream transcription factors such as TFAM to enhance the energy metabolism.In addition,we also found that simvastatin can induce apoptosis in skeletal muscle,the main basis is that the ratio of Bcl/Bax in gastrocnemius muscle of mice decreased significantly,while astragaloside can effectively inhibit the apoptosis induced by simvastatin.Moreover,we also found that the combination of astragaloside and simvastatin did not affect the lipid-lowering effect of simvastatin.Conclusion:Astragaloside can effectively improve the muscle damage caused by simvastatin.Its potential mechanism is that astragaloside can promote the phosphorylation of AMPK and activate PGC-1?,thus up regulating the expression of Nrf1 and its downstream transcription factors to enhance energy metabolism.Furthermore,astragaloside did not affect the lipid-lowering effect of simvastatin.