运动和EGCG对Ⅱ型糖尿病大鼠海马线粒体功能的改善作用及机制研究
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摘要
研究目的：线粒体功能损伤是神经元损伤和产生认知障碍的重要机制之一，对病理状态下神经元线粒体功能损伤改善研究有着重要的意义。本研究通过运动和EGCG给药单独或共同干预，从SIRT1/PGC-1通路及下游蛋白表达的角度探讨不同干预方式在改善II型糖尿病大鼠海马线粒体功能损伤中的作用，从线粒体的生物合成、线粒体的抗氧化应激能力、线粒体融合/分裂和线粒体自噬等方面讨论其改善作用和机制，为运动和EGCG的神经保护作用提供理论和实验依据。
研究方法：同批次SPF级6周龄雄性SD大鼠152只，随机分成正常对照组（42只）和高脂饮食组（110只）；正常对照组随机分为三组：4周正常对照组（12只）、8周正常对照组（12只）和12周正常对照组（18只）；高脂饮食组通过6周高脂饮食加小剂量链脲佐菌素（STZ，30mg/kgbw）诱导II型糖尿病（T2DM）大鼠模型，观察4周、8周和12周的大鼠海马线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ、Ⅳ和Na+-K+-ATP酶、Ca2+-ATP酶活性的变化。将诱导产生的II型糖尿病大鼠分为糖尿病对照组（16只）、糖尿病运动组（18只）、糖尿病给药组（19只）和糖尿病运动给药组（18只）四组，进行12周游泳运动和EGCG给药单独或共同干预，采用western blot检测大鼠海马SIRT1、PGC-1、NRF1、NRF2、TFAM、HO-1、NIX、BNIP3、PINK1和Parkin蛋白表达量；采用RT-PCR检测海马mtDNA的拷贝量；检测线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ、Ⅳ和Na+-K+-ATP酶、Ca2+-ATP酶活性的变化。
研究结果：
112周的糖尿病大鼠海马线粒体呼吸链复合酶Ⅰ、Ⅱ、Ⅲ、Ⅳ以及Na+-K+-ATP酶、Ca2+-ATP酶活性较正常对照组均显著降低（P＜0.01）；运动和EGCG给药单独或共同干预能不同程度提高II型糖尿病大鼠海马线粒体呼吸链复合酶Ⅰ、Ⅱ、Ⅲ、Ⅳ和Na+-K+-ATP酶、Ca2+-ATP酶活性（P＜0.05或P＜0.01）。
2糖尿病对照组大鼠海马SIRT1、PGC-1、NRF1、TFAM、NRF2、HO-1和mtDNA均显著低于正常对照组（P＜0.01）；运动和EGCG给药单独或共同干预能不同程度提高SIRT1、PGC-1、NRF1、TFAM、NRF2、HO-1蛋白的表达和mtDNA拷贝量。
3糖尿病对照组大鼠海马Mfn2、OPA1蛋白表达显著低于正常对照组（P＜0.01），Drp1和Fis1蛋白表达显著高于正常对照组（P＜0.01）；运动和EGCG给药单独或共同干预可不同程度提高大鼠海马Mfn2和OPA1蛋白表达（P＜0.05或P＜0.01），运动和EGCG给药单独或共同干预可不同程度降低Drp1和Fis1蛋白表达（P＜0.05或P＜0.01）。
4糖尿病对照组大鼠海马NIX、BNIP3较正常对照组均显著降低（P＜0.05），Parkin较正常对照组显著升高（P＜0.05），PINK1较正常对照组无显著差异（P＞0.05）；运动和EGCG给药单独或共同干预可不同程度提高海马NIX、BNIP3蛋白表达（P＜0.05或P＜0.01），而PINK1、Parkin蛋白表达较糖尿病对照组无显著差异（P＞0.05）。
512周的游泳训练和EGCG给药单独或共同干预对II型糖尿病大鼠海马线粒体呼吸链酶和ATP酶活性下降均有不同程度的改善作用，且二者共同干预的改善效果明显好于单一因素干预，表明二者有叠加作用。
结论：
1运动和EGCG给药单独或共同干预，能不同程度改善II型糖尿病大鼠海马线粒体呼吸链复合物酶活性和能量代谢功能。
2运动和EGCG给药单独或共同干预能不同程度的提高II型糖尿病大鼠海马SIRT1/PGC-1通路效应，改善了海马线粒体生物合成能力，提高了线粒体抗氧化酶表达。
3运动和EGCG给药单独或共同干预能提高II型糖尿病大鼠海马Mfn2和OPA1蛋白的表达，降低Drp1和Fis1蛋白表达，改善海马线粒体的融合/分裂失衡状态。
4运动和EGCG给药单独或共同干预能够提高II型糖尿病大鼠海马NIX和BNIP3蛋白表达，改善海马线粒体自噬能力。
5运动联合EGCG是干预糖尿病中枢神经系统线粒体功能障碍的有效策略；SIRT1/PGC-1通路可作为运动和药物改善II型糖尿病海马线粒体功能的靶点。
Objective:
Reduced mitochondrial function is a major cause damage to the central nervoussystem and produces cognitive impairment. Research on improving the function ofneuronal mitochondrial damage under pathological conditions has importantsignificance. In this research，type2diabetic rats were induced by6weeks high-fat dietand low-dose streptozotocin-treated （STZ，30mg/kg），to study the eimprovement of12weeks of swimming training and EGCG separately or jointly intervention on on type2diabetic rats hippocampal mitochondrial dysfunction, studid theSIRT1/PGC-1pathway and downstream protein effects in it. discussed the effect andmechanism from Biosynthesis of mitochondria, oxidative stress resistance,mitochondrial fission and fusion, mitochondrial Autophagy to discuss its effect andmechanisms. The experimental results of present study support the neuroprotection ofexercise and EGCG,and also provide a new strategy of preventing and curingdiabetic encephalopathy.
Methods:Type2diabetic rat model was successfully established,4weeks,8weeksand12weeks of rat hippocampus mitochondrial respiratory chain complexes Ⅰ, Ⅱ, Ⅲ,Ⅳ and Na+-K+-ATPase、Ca2+-ATPase activity was explored. The diabetic rats weredivided into diabetic control group,the diabetes exercise group,the diabetes druggroup,the diabetes exercise and drug jiotly group, For12weeks of exercise and EGCGseparately or jointly intervention. Western blot was used to detect the rat hippocampalSIRT1, PGC-1, NRF1, NRF2, TFAM, HO-1, NIX, BNIP3, PINK1and Parkin proteinexpression; RT-PCR was used to detect hippocampal mtDNA copy amount.The changesof rathippocampal mitochondrial respiratory chain complexes Ⅰ, Ⅱ, Ⅲ, Ⅳ and Na+ -K+atpase, Ca2+atpase activity were researched.
Results:
112weeks diabetic rats hippocampus mitochondrial respiratory chain enzyme Ⅰ、Ⅱ、Ⅲ、Ⅳ, Ca2+-ATPase activity and Na+-K+-ATP ase were showing a significantreduction in decline （P<0.01）;Exercise and EGCG medication, separately or jointlyintervention,could improve diabetes rats,hippocampus mitochondrial respiratorychain complex enzymes Ⅰ, Ⅱ, Ⅲ, Ⅳ and Na+-k+ATPase, Ca2+-ATPase activity indifferent level （P <0.05or P <0.01）.
2Diabetes control group rats，hippocampal SIRT1, PGC-1, NRF1, TFAM andmtDNA, NRF2, HO-1were significantly lower than normal control group（P <0.01）;Exercise and EGCG medication separately or jointly intervention could improve theSIRT1, PGC-1, NRF1, TFAM, NRF2, HO-1protein expression and mtDNA copies indifferent level.
3Diabetes control group rats hippocampal Mfn2, OPA1protein expression wassignificantly lower than normal control group （P <0.01）, and Drp1Fis1proteinexpression was significantly higher than that of normal control group （P <0.01）;Exercise and EGCG medication separately or jointly intervention could improve therat hippocampal Mfn2and OPA1protein expression in different level（P <0.05or P <0.01）, could reduce Drp1and Fis1protein expression in different level （P <0.05orP <0.01）.
4Diabetes control group rats hippocampal NIX, BNIP3protein expressioncompared with were significantly lower （P <0.05）, Parkin significantly increasedcompared with normal control group （P <0.05）, PINK1protein expression comparedwith normal control group was no significant difference （P>0.05）; Exercise andEGCG medication separately or jointly intervention could improve the hippocampusNIX, different level BNIP3protein expression （P <0.05or P <0.01）, PINK1, Parkinprotein expression was no significant difference than diabetes control group（P>0.05）.
512weeks of exercise and EGCG medication separately or jointly interventioncould improve Type2diabetes rat hippocampal mitochondria function. the jointlyintervention was ignificantly better than a single factor, indicating the jointly intervention have additive effects.
Conclusions:
112weeks of exercise training and EGCG medication separately or jointlyintervention can improve diabetes rat hippocampus mitochondrial respiratory chaincomplex enzymes activity，increase the ATP enzyme activity，improve the energymetabolism of mitochondria.
2Exercise and EGCG medication separately or jointly intervention couldinhance type2diabetic rats hippocampal SIRT1/PGC-1pathway effect, improve theability of the biosynthesis of mitochondria and mitochondrial antioxidant capacity.
312weeks of exercise and EGCG medication separately or jointly interventioncan improve the type2diabetic rats hippocampal Mfn2and OPA1protein expression，reduce Drp1and Fis1protein expression and improve diabetic rats hippocampalmitochondria imbalance of fusion and fission protein.
412weeks of exercise training and EGCG medication separately or jointlyintervention could enhance the type2diabetic rats hippocampal NIX and BNIP3expression, improve rats,hippocampus mitochondrial autophagy ability，maintain thestability of the mitochondrial quality and quantity.
5Exercise and EGCG medication jointly intervention may be an effectiveintervention strategies in mitochondrial dysfunction. SIRT1/PGC-1biologicalpathways could be an important target for regulation of mitochondrial function to thediabete，s prevention and treatment of the nervous system.
研究方法：同批次SPF级6周龄雄性SD大鼠152只，随机分成正常对照组（42只）和高脂饮食组（110只）；正常对照组随机分为三组：4周正常对照组（12只）、8周正常对照组（12只）和12周正常对照组（18只）；高脂饮食组通过6周高脂饮食加小剂量链脲佐菌素（STZ，30mg/kgbw）诱导II型糖尿病（T2DM）大鼠模型，观察4周、8周和12周的大鼠海马线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ、Ⅳ和Na+-K+-ATP酶、Ca2+-ATP酶活性的变化。将诱导产生的II型糖尿病大鼠分为糖尿病对照组（16只）、糖尿病运动组（18只）、糖尿病给药组（19只）和糖尿病运动给药组（18只）四组，进行12周游泳运动和EGCG给药单独或共同干预，采用western blot检测大鼠海马SIRT1、PGC-1、NRF1、NRF2、TFAM、HO-1、NIX、BNIP3、PINK1和Parkin蛋白表达量；采用RT-PCR检测海马mtDNA的拷贝量；检测线粒体呼吸链复合物Ⅰ、Ⅱ、Ⅲ、Ⅳ和Na+-K+-ATP酶、Ca2+-ATP酶活性的变化。
研究结果：
112周的糖尿病大鼠海马线粒体呼吸链复合酶Ⅰ、Ⅱ、Ⅲ、Ⅳ以及Na+-K+-ATP酶、Ca2+-ATP酶活性较正常对照组均显著降低（P＜0.01）；运动和EGCG给药单独或共同干预能不同程度提高II型糖尿病大鼠海马线粒体呼吸链复合酶Ⅰ、Ⅱ、Ⅲ、Ⅳ和Na+-K+-ATP酶、Ca2+-ATP酶活性（P＜0.05或P＜0.01）。
2糖尿病对照组大鼠海马SIRT1、PGC-1、NRF1、TFAM、NRF2、HO-1和mtDNA均显著低于正常对照组（P＜0.01）；运动和EGCG给药单独或共同干预能不同程度提高SIRT1、PGC-1、NRF1、TFAM、NRF2、HO-1蛋白的表达和mtDNA拷贝量。
3糖尿病对照组大鼠海马Mfn2、OPA1蛋白表达显著低于正常对照组（P＜0.01），Drp1和Fis1蛋白表达显著高于正常对照组（P＜0.01）；运动和EGCG给药单独或共同干预可不同程度提高大鼠海马Mfn2和OPA1蛋白表达（P＜0.05或P＜0.01），运动和EGCG给药单独或共同干预可不同程度降低Drp1和Fis1蛋白表达（P＜0.05或P＜0.01）。
4糖尿病对照组大鼠海马NIX、BNIP3较正常对照组均显著降低（P＜0.05），Parkin较正常对照组显著升高（P＜0.05），PINK1较正常对照组无显著差异（P＞0.05）；运动和EGCG给药单独或共同干预可不同程度提高海马NIX、BNIP3蛋白表达（P＜0.05或P＜0.01），而PINK1、Parkin蛋白表达较糖尿病对照组无显著差异（P＞0.05）。
512周的游泳训练和EGCG给药单独或共同干预对II型糖尿病大鼠海马线粒体呼吸链酶和ATP酶活性下降均有不同程度的改善作用，且二者共同干预的改善效果明显好于单一因素干预，表明二者有叠加作用。
结论：
1运动和EGCG给药单独或共同干预，能不同程度改善II型糖尿病大鼠海马线粒体呼吸链复合物酶活性和能量代谢功能。
2运动和EGCG给药单独或共同干预能不同程度的提高II型糖尿病大鼠海马SIRT1/PGC-1通路效应，改善了海马线粒体生物合成能力，提高了线粒体抗氧化酶表达。
3运动和EGCG给药单独或共同干预能提高II型糖尿病大鼠海马Mfn2和OPA1蛋白的表达，降低Drp1和Fis1蛋白表达，改善海马线粒体的融合/分裂失衡状态。
4运动和EGCG给药单独或共同干预能够提高II型糖尿病大鼠海马NIX和BNIP3蛋白表达，改善海马线粒体自噬能力。
5运动联合EGCG是干预糖尿病中枢神经系统线粒体功能障碍的有效策略；SIRT1/PGC-1通路可作为运动和药物改善II型糖尿病海马线粒体功能的靶点。
Objective:
Reduced mitochondrial function is a major cause damage to the central nervoussystem and produces cognitive impairment. Research on improving the function ofneuronal mitochondrial damage under pathological conditions has importantsignificance. In this research，type2diabetic rats were induced by6weeks high-fat dietand low-dose streptozotocin-treated （STZ，30mg/kg），to study the eimprovement of12weeks of swimming training and EGCG separately or jointly intervention on on type2diabetic rats hippocampal mitochondrial dysfunction, studid theSIRT1/PGC-1pathway and downstream protein effects in it. discussed the effect andmechanism from Biosynthesis of mitochondria, oxidative stress resistance,mitochondrial fission and fusion, mitochondrial Autophagy to discuss its effect andmechanisms. The experimental results of present study support the neuroprotection ofexercise and EGCG,and also provide a new strategy of preventing and curingdiabetic encephalopathy.
Methods:Type2diabetic rat model was successfully established,4weeks,8weeksand12weeks of rat hippocampus mitochondrial respiratory chain complexes Ⅰ, Ⅱ, Ⅲ,Ⅳ and Na+-K+-ATPase、Ca2+-ATPase activity was explored. The diabetic rats weredivided into diabetic control group,the diabetes exercise group,the diabetes druggroup,the diabetes exercise and drug jiotly group, For12weeks of exercise and EGCGseparately or jointly intervention. Western blot was used to detect the rat hippocampalSIRT1, PGC-1, NRF1, NRF2, TFAM, HO-1, NIX, BNIP3, PINK1and Parkin proteinexpression; RT-PCR was used to detect hippocampal mtDNA copy amount.The changesof rathippocampal mitochondrial respiratory chain complexes Ⅰ, Ⅱ, Ⅲ, Ⅳ and Na+ -K+atpase, Ca2+atpase activity were researched.
Results:
112weeks diabetic rats hippocampus mitochondrial respiratory chain enzyme Ⅰ、Ⅱ、Ⅲ、Ⅳ, Ca2+-ATPase activity and Na+-K+-ATP ase were showing a significantreduction in decline （P<0.01）;Exercise and EGCG medication, separately or jointlyintervention,could improve diabetes rats,hippocampus mitochondrial respiratorychain complex enzymes Ⅰ, Ⅱ, Ⅲ, Ⅳ and Na+-k+ATPase, Ca2+-ATPase activity indifferent level （P <0.05or P <0.01）.
2Diabetes control group rats，hippocampal SIRT1, PGC-1, NRF1, TFAM andmtDNA, NRF2, HO-1were significantly lower than normal control group（P <0.01）;Exercise and EGCG medication separately or jointly intervention could improve theSIRT1, PGC-1, NRF1, TFAM, NRF2, HO-1protein expression and mtDNA copies indifferent level.
3Diabetes control group rats hippocampal Mfn2, OPA1protein expression wassignificantly lower than normal control group （P <0.01）, and Drp1Fis1proteinexpression was significantly higher than that of normal control group （P <0.01）;Exercise and EGCG medication separately or jointly intervention could improve therat hippocampal Mfn2and OPA1protein expression in different level（P <0.05or P <0.01）, could reduce Drp1and Fis1protein expression in different level （P <0.05orP <0.01）.
4Diabetes control group rats hippocampal NIX, BNIP3protein expressioncompared with were significantly lower （P <0.05）, Parkin significantly increasedcompared with normal control group （P <0.05）, PINK1protein expression comparedwith normal control group was no significant difference （P>0.05）; Exercise andEGCG medication separately or jointly intervention could improve the hippocampusNIX, different level BNIP3protein expression （P <0.05or P <0.01）, PINK1, Parkinprotein expression was no significant difference than diabetes control group（P>0.05）.
512weeks of exercise and EGCG medication separately or jointly interventioncould improve Type2diabetes rat hippocampal mitochondria function. the jointlyintervention was ignificantly better than a single factor, indicating the jointly intervention have additive effects.
Conclusions:
112weeks of exercise training and EGCG medication separately or jointlyintervention can improve diabetes rat hippocampus mitochondrial respiratory chaincomplex enzymes activity，increase the ATP enzyme activity，improve the energymetabolism of mitochondria.
2Exercise and EGCG medication separately or jointly intervention couldinhance type2diabetic rats hippocampal SIRT1/PGC-1pathway effect, improve theability of the biosynthesis of mitochondria and mitochondrial antioxidant capacity.
312weeks of exercise and EGCG medication separately or jointly interventioncan improve the type2diabetic rats hippocampal Mfn2and OPA1protein expression，reduce Drp1and Fis1protein expression and improve diabetic rats hippocampalmitochondria imbalance of fusion and fission protein.
412weeks of exercise training and EGCG medication separately or jointlyintervention could enhance the type2diabetic rats hippocampal NIX and BNIP3expression, improve rats,hippocampus mitochondrial autophagy ability，maintain thestability of the mitochondrial quality and quantity.
5Exercise and EGCG medication jointly intervention may be an effectiveintervention strategies in mitochondrial dysfunction. SIRT1/PGC-1biologicalpathways could be an important target for regulation of mitochondrial function to thediabete，s prevention and treatment of the nervous system.
引文
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