The Role And Mechanism Of SIRT1 In Exercise Alleviating The Decline Of Learning And Memory In T2DM Mice

Object:Type 2 diabetes mellitus(T2DM)decreased learning and memory ability seriously affects the quality of life of patients with T2DM.The expression of brain derived neurotrophic factor(BDNF)can effectively improve the decline of learning and memory.Previous studies have shown that exercise can improve the impairment of learning and memory in T2DM,but the mechanism is unclear.Studies have pointed out that silent mating type information regulation 2 homolog 1(SIRT1)can increase the expression of BDNF in the brain.In this study,by observing the effect of treadmill exercise on the expression of BDNF in the hippocampus of T2DM model mice and the ability of learning and memory,to explore whether the positive effect mechanism of exercise on T2DM model mice is SIRT1-dependent.Method:Twenty-four C57BL/6 mice were selected and fed with high-fat diet combined with intraperitoneal injection of STZ to construct a T2DM model.The mice were randomly divided into normal control group(C group),T2DM group(T group),and T2DM exercise group(E group),T2DM exercise and SIRT1 inhibitor injection group(NAM group),6 animals in each group.The E and NAM groups performed 8 weeks of moderate-intensity aerobic treadmill exercise,5 days a week,once a day,each exercise at 60%Smax for 27 minutes(5 minutes before and after exercise with 40%Smax intensity for warm-up And relaxation exercise).The learning and memory abilities of mice were detected by water maze,SIRT1 and its downstream related signal pathways(PGC-1α/FNDC5)and BDNF protein expression in the hippocampus were detected by Western blootting method,and SIRT1 and its downstream related signals in the hippocampus were detected by RT-PCR method Pathway and BDNF mRNA expression.Results:(1)Compared with mice in group C,mice in group T had significantly lower body weight(p<0.01),lower fasting insulin levels(p<0.001),and higher fasting blood glucose(p<0.001);during the 5-day positioning navigation experiment,it showed a longer escape latency(p<0.05)and a shorter platform quadrant time percentage(p<0.05);in the space exploration experiment on the 6th day,the number of crossing platforms was significantly reduced(p<0.05);BDNF(p<0.01),SIRT1,PGC-1a protein and mRNA expression levels were significantly reduced(p<0.05),although the protein and mRNA expression levels of FNDC5 were reduced,hasn’t statistical difference(p>0.05).(2)Compared with the T group,the body weight(p<0.05)and fasting blood insulin level(p<0.001)of the E group were significantly increased,and the fasting blood glucose level was significantly reduced(p<0.05);the escape latency was in the 4-5th Days are significantly reduced(p<0.05),and the percentage of platform quadrant time is significantly increased(p<0.05);in the space exploration experiment on the 6th day,the number of crossing platforms is significantly increased(P<0.05);BDNF,SIRT1(p<0.01),PGC-1a protein level and mRNA level increased significantly(p<0.05).Although the protein level and mRNA level of FNDC5 increased,hasn’t statistical difference(p>0.05).(3)Compared with the E group,the NAM group’s body weight,blood insulin significantly decreased(p<0.05),and the blood glucose level significantly increased(p<0.05);during the positioning sailing experiment on the 4-5th day,the escape latency increased significantly(p<0.05),the platform quadrant time percentage was significantly reduced(p<0.05);in the space exploration experiment on the 6th day,the number of crossing platforms was significantly reduced(p<0.05);the protein and mRNA levels of BDNF,SIRT1,PGC-1α were significantly decrease(p<0.05),although the protein level and mRNA level of FNDC5 decreased,hasn’t statistical difference(p>0.05).Conclusion:8 weeks of moderate-intensity treadmill exercise may increase the expression of BDNF in T2DM mice by activating SIRT1,and improve the learning and memory ability of T2DM mice.