Molecular Mechanism Of Exercise Training Intervention For Insulin Resistance: A Potential Role Of Skeletal Muscle Mitochondrial Dynamics

Aims:To investigate the effects of mitochondrial dynamics (fusion and fission) and function on pathogenesis of insulin resistance induced by high-fat-diet and the mechanism of long-term aerobic exercise improve insulin resistance in mice. The insulin resistant mice model were created. To elucidate the cellular and molecular mechanisms responsible for insulin resistance by study the mitochondrial fusion and fission balance in the pathogenesis of insulin resistance induced by high-fat-diet and the effect of the exercise intervention. This study aims to provide potential targets and thoery evidence to the treatment and exercise intervention to prevention of insulin resistance and type 2 Diabetes Mellitus.Methods:To create insulin resistant mice model,80 male C57BL/6 mice divided into 2 groups:Normal chow control (N) group and High-Fat-diet (H) group. The fast serum insulin and OGTT were detected and HOMA-IR was calculated to evaluate the insulin sensitivity. Then the H group divided into 4 groups:continued high-fat-diet (HHS) group, continued high-fat-diet plus training (HHE) group, change to normal chow (HNS) group, change to normal chow plus training (HNE) group. The N group divided into 2 groups:continued normal chow (NNS) group and continued normal chow (NNE) plus training group. The aerobic training groups commit 8 weeks treadmill training (13m/min,60 min, per day for 5 days per week). The mitochondrial morphology were studied with electron-micrograph. The fast serum insulin was measured by ELISA kit. Respiratory control ratio and ATP synthesis activity in isolated mitochondria were detected. Skeletal muscle mRNA and Protein levels of Mfn2、Opa1、Drp1、Fis1、Glut4 were measured by Realtime PCR and Westernblot respectively. The PGC1-αmRNA was also measured.Results:1) After 8 weeks High-Fat-Diet, the body weight and Visceral Fat of High-Fat-Diet (H) group mice were higher than mice of Normal chow group. The fast serum insulin, HOMA-IR and glucose levels at 15min、30min、60min、90min、120mi、180min in OGTT and AUCOGTT increased.2) Compared with the mice of NNS group, the size and number of skeletal muscle mitochondria in mice of HHS group are decreased. The state 3 respiratory rate, respiratory control ratio and ATP synthesis activity were decreased. The expression of GLUT4 and genes for mitochondrial fusion decreased, and the expression of genes for mitochondrial fission increased.3) Changing the high-fat-diet to normal chow could improve the insulin resistance in mice. There were fewer lipid deposit in skeletal muscle, and the size and number of mitochondria increased. The expression of GLUT4 and genes for mitochondrial fusion increased, and the expression of genes for mitochondrial fission decreased.4) 8 weeks aerobic training can significantly reverse insulin resistance induced by high-fat-diet in mice. The size and number of skeletal muscle mitochondria increased. The state 3 respiratory rate, respiratory control ratio and ATP synthesis activity increased, too. The expression of GLUT4 and genes for mitochondrial fusion and fission increased.Conclusions:1) Insulin resistance could be induced by prolonged high fat diet in mice. The insulin resistant mice showed high fast serum insulin level, glucose intolerated, accompanied by obesity and lipid deposits in skeletal muscle.2) The respiratory function and ATP synthesis activity of skeletal muscle mitochondria decreased in insulin resistant mice. The expression of genes for mitochondrial fusion decreased and the expression of genes for fission increased. The number and size of mitochondria decreased, too. The IR mice skeletal muscle mitochondria showed decreased biogenesis, inclined to fission and dysfunction.3) Long time aerobic training can improve the insulin resistant in mice. The mitochondrial respiratory function and ATP synthesis activity were enhanced. The expression of genes for mitochondrial fusion and fission increased. The number and size of mitochondria increased, too. The skeletal muscle mitochondria in aerobic training mice showed more active biogenesis fission and dysfunction and improved function.