摘要
研究目的:本研究建立心梗致慢性心衰动物模型,观察心衰及心衰后有氧运动对心肌线粒体生物力能学、生物合成与融合分裂的变化影响,探讨其分子生理学适应机制。
研究方法:雄性wistar大鼠,心梗组开胸后结扎左冠状动脉前降支,造成心梗模型,假手术组开胸但不结扎冠状动脉,其余处理与心梗组相同。术后4周,心梗组和假手术组再随机分为心梗安静组(MI),心梗运动组(MI+E),假手术安静组(Sham),假手术运动组(Sham+E)。运动组进行跑台训练,运动强度14米/分钟,每次40分钟,每周训练5天,共训练8周。术后12周,超声心动图检查各组大鼠心率(HR),心室收缩末期内径(LVIDs),舒张末期内径(LVIDd)和心功能指标射血分数(EF),心输出量(CO)。提取心肌线粒体测定态3、态4呼吸和呼吸控制比(RCR),ATP生成活力。Western blot检查心肌线粒体生物合成调控因子PGC-1α,线粒体蛋白COⅩⅣ、COⅪ,线粒体分裂蛋白fis-1,融合蛋白mfn-2的蛋白表达。透射电镜观察各组心肌线粒体形态数量。
研究结果:术后12周,假手术运动组LVIDs,LVIDd,EF,CO与假手术安静组比较无明显变化,态3呼吸,RCR,ATP生成活力高于假手术安静组,PGC-1α,COⅩⅣ、COⅪ蛋白表达无明显变化,fis-1,mfn-2表达增加。心梗安静组与假手术安静组比较,LVIDs,LVIDd增加,EF,CO降低,态4呼吸增加,RCR,ATP生成活力降低,PGC-1α蛋白表达无明显变化,COⅩⅣ、COⅪ蛋白表达增加,fis-1蛋白表达增加,mfn-2表达降低,心肌线粒体比例增加。心梗运动组与心梗安静组比较LVIDs,LVIDd增加,EF降低,CO增加,HR增加,态3呼吸,RCR,ATP生成活力增加,PGC-1α、COⅩⅣ、COⅪ蛋白表达增加,fis-1蛋白表达降低,mfn-2蛋白表达降低,心肌线粒体比例增加。
结论:1.心衰后心肌线粒体分裂融合的动态平衡被打破,线粒体趋向分裂,融合降低,线粒体生物合成增加,但线粒体功能下降。2.低强度有氧运动对假手术大鼠安静时心功能无明显影响,对心肌线粒体的生物合成没有明显的促进作用,但可提高心肌线粒体的呼吸效率和线粒体融合分裂的水平。3.有氧运动能促进心衰后大鼠心肌线粒体的功能,促进其心肌线粒体生物合成。4.心衰后和心衰后运动引起心肌线粒体数量的增加,可能是对心衰后心肌收缩能力下降,线粒体功能下降以及心肌能量需求增加的一种代偿性反应。但是,线粒体生物合成的增加并不能完全代偿心衰后心功能的下降,并有可能加重心肌重构。5.心肌线粒体对运动的适应中,线粒体的生物合成不是首选的途径,而是首先通过调节线粒体的功能状态来达到对运动的适应。心肌线粒体对运动的适应中,线粒体的融合分裂过程是最先参与动员的机制之一,对线粒体的功能状态可能有重要的影响。
Aims:Mitochondrial dysfunction is a major factor in heart failure(HF).The aim of present study was to to investigate 1) the mitochondrial function, mitochondrial biogenesis and mitochondrial dynamics in the failing myocardium post myocardial infarction.2) the effects of aerobic exercise on the cardiac function and the mitochondrial function,biogenesis and dynamics in the cardiac muscle after myocardial infarction.
Methods:Myocardial infarction(MI) was obtained by left descending coronary artery ligation.Sham operation was performed in another group without coranay ligation.4 weeks after the operation,the animals were divided into 4 groups:sham operatin control group(sham),sham operation plus exercise group(sham+E), myocardial infarction group(MI),myocardial infarction plus exercise group(MI+E). Exercise groups were trained on treadmill for 8 weeks,5 days a week.14m/min, 40min/day.LVIDs,LVIDd,ejection fraction(EF),cardial output(CO),heart rate (HR) were measured with M-mode echocardiograms.Mitochondrial oxygen consumption was measured in respiration of state 3(R3) and state 4(R4),the respiratory control ration(RCR) was calculated.Protein expression of PGC-1α, (involved in the regulation of mitochondrial biogenesis),COXIV,COXI(marker of mitochondrial biogenesis),fis-1(involved in mitochondrial fission),mfn-2(involved in mitochondrial fusion) were measured with western blot.Histological studies were performed with the stain methods of HE and Masson's trichrome.Ultra structure of non-infarcted left-ventricular tissue and skeletal muscle were studied with electron micrograph.
Results:1.There is no difference in theLVIDs,LVIDd,EF,CO,PGC-1α, COXIV,COXI expression between sham+E group and sham group.R3,RCR,fis-1, mfn-2 protein expression were higher in sham+E group compared with sham group. 2.Compared with sham group,MI group had higher R4,lower RCR,higher LVIDs, LVIDd,lower EF,CO,higher COXIV,COXI,fis-1 expression,lower mfn-2 expression,higher mitochondrial volume.3.Compared with MI group,MI+E group had higherLVIDs,LVIDd,CO,HR,lower EF,higher R4,RCR,higher COXIV, COXI protein expression,lower fis-1,mfn-2 expression,higher mitochondrial volume.
Conclusions:1.Aerobic exercise training enhanced the mitochondrial function and proliferation in the myocardium and skeletal muscle of rats post myocardial infarction.Aerobic exercise training may have a favorable effect on the rats post myocardial infarction.2.Moderate aerobic exercise can not elevate the cardiac function at rest of the normal rats,can not enhance the mitochondrial biogenesis of cardiac muscle for normal rats.But aerobic exercise training enhanced the mitochondrial function and dynamics.3.After myocardial infarction,the cardiac muscle mitochondria function were impaired,mitochondrial proliferation were triggered,mitochondrial mitochondria dynamics balance was impaired, mitochondrial fission was elevated and fusion was depressed.4.Mitochondrial functional status instead of mitochondrial biogenesis participates the adaptation of cardiac muscle to aerobic training in the early stage.5.Mitochondrial dynamics may play an important role in the regulation of mitochondrial function status.6.Cardiac remodeling post myocardial infarction may be relevant to cardiac muscle mitochondrial biogenesis.
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