AMP激活的蛋白激酶在COPD大鼠骨骼肌线粒体生物合成调控中的作用机制研究
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摘要
第一部分大鼠COPD模型建立及干预
背景和目的：
慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是一种以气流受限为特征的慢性气道疾病,同时也是一种涉及多器官受损的全身疾病。近年来国内外研究发现,部分运动受限的COPD患者表现为明显的骨骼肌功能障碍。对中、重度COPD患者,骨骼肌的消耗成为预计患者病死率的重要指标之一。
COPD的骨骼肌功能障碍形成机制复杂,系统性炎症在COPD患者中的存在已被广泛接受,有人认为炎症是COPD患者骨骼肌功能障碍的始动因素。其中肿瘤坏死因子-α(Tumor necrosis factor-a, TNF-a)作为一种重要炎症介质已被证明参与了COPD的炎症过程。
线粒体是骨骼肌运动所需能量的生成场所,也是活性氧(ROS)产生的主要场所,同时也处于细胞凋亡的中心环节。因此,线粒体功能障碍在COPD的骨骼肌功能障碍中越来越受到重视。已有研究发现,中重度COPD患者出现运动性骨骼肌萎缩、骨骼肌线粒体密度减少及结构异常。
我们拟通过建立COPD大鼠模型,观察COPD模型大鼠骨骼肌形态学变化及电镜下骨骼肌纤维与线粒体变化,同时给予白藜芦醇及AMP激活的蛋白激酶(Adenosine5'-monophosphate (AMP)-activated protein kinase, AMPK)激动剂干预。评估外周血及骨骼肌TNF-a水平与骨骼肌与线粒体的结构形态改变的关系,为炎症在COPD骨骼肌功能障碍中的损伤作用机制提供实验依据。
方法：
1.COPD大鼠模型制备用两次气管内注入脂多糖(LPS)和反复烟熏的方法制作COPD大鼠模型。
2.分组与处理雄性SD大鼠随机分为对照组、COPD模型组、AICAR (AMPK特异性激动剂)组和白藜芦醇组,对照组和模型组分别给予生理盐水、AICAR、白藜芦醇。
3.肺功能采用无束缚小动物肺功能仪(Buxco, USA)测定大鼠肺功能变化。
4.肺和骨骼肌病理采用HE、Masson染色光学显微镜下观察各组肺脏和骨骼肌的病理变化。及电镜观察骨骼肌与线粒体的超微结构改变。
结果：
1.各实验组大鼠行为变化模型组及各治疗组大鼠早期出现躁动不安、咳嗽、气急、、进食进水量逐渐减少等表现。正常对照组则始终未见上述表现。各组体重改变差异无显著性。
2.各实验组大鼠肺功能变化与对照组比较,模型组大鼠PEF明显降低(P<0.01),VT明显降低(P<0.05),EF50明显降低(P<0.05)。AICAR和白藜芦醇组PEF、均较模型组明显升高(P<0.05,P<0.01)。AICAR和白藜芦醇组VT均较模型组明显升高、EF50(P<0.05)。AICAR和白藜芦醇组EF50均较模型组明显升高(P<0.05)AICAR和白藜芦醇组间比较差异无统计学意义(P>0.05)。
3.大鼠肺组织病理变化COPD模型组可见广泛肺泡壁增厚、破坏,肺泡破裂、融合,小气道纤毛脱落,气腔狭窄,小血管壁增厚。AICAR组肺组织可见中量炎症细胞浸润,肺泡壁破坏、肺泡融合,肺泡腔增大；白藜芦醇组肺组织可见中量炎症细胞浸润,肺泡壁破坏、小气道纤毛脱落,气腔狭窄。
4.骨骼肌细胞形态学观察COPD模型组大鼠骨骼肌细胞轻度萎缩,胶原纤维沉积较对照组明显增多。白藜芦醇和AICAR组大鼠组骨骼肌细胞较COPD模型组大鼠胶原纤维沉积减少。透射电镜下观察显示：模型组大鼠的小腿三头肌线粒体减少,出现肿胀,水性变及空泡化,内膜、嵴破坏溶解改变；白藜芦醇组及AICAR组大鼠的小腿三头肌线粒体结构尚完整,肌丝完整,肌原纤维排列整齐,分布正常。
结论：
1.两次气管内注入脂多糖(LPS)和反复烟熏的方法可成功制作COPD大鼠模型。
2. COPD模型大鼠骨骼肌存在骨骼肌炎症及线粒体损伤。
3. AICAR及白藜芦醇可以改善COPD模型大鼠骨骼肌炎症反应,减轻线粒体结构损伤。
第二部分AMPK对COPD大鼠骨骼肌线粒体合成调控中的作用及白藜芦醇作用机制探讨
背景和目的：
近年来国内外研究发现,部分运动受限的COPD患者表现为明显的骨骼肌功能障碍。COPD的骨骼肌功能障碍形成机制复杂,系统性炎症在COPD患者中的存在已被广泛接受,TNF-α作为一种重要炎症介质已被证明参与了COPD的炎症过程。
AMPK作为真核生物细胞中一个重要的蛋白激酶,参与细胞的能量代谢过程,其通过调控代谢相关酶起作用。国内外研究发现AMPK的下游靶蛋白参与能量代谢调节有关。但是AMPK是否参与炎症介导的COPD骨骼肌线粒体生物合成障碍目前一无所知。
本研究拟通过观察大鼠外周血与骨骼肌TNF-α水平、骨骼肌AMPK表达、PGC-1α及线粒体生物合成相关基因表达的变化,进而探讨炎症状态下COPD模型大鼠骨骼肌线粒体合成的的影响,同时给予AMPK激动剂及白藜芦醇干预后观察PGC-1α变化及对骨骼肌线粒体生物合成的影响,为治疗COPD骨骼肌障碍提供新的理论基础。
方法：
1. COPD大鼠模型制备与分组与处理同第一部分。
2.取材与处理采用酶联免疫吸附(ELISA)法测定血清TNF-a浓度；小腿三头肌留取组织匀浆,取上清液采用ELISA法检测TNF-a浓度；采用荧光定量PCR分析检测AMPK、NRF-1、PGC-1α、Tfam、COX ⅣmRNA表达；采用Western blotting检测AMPK, TNF-α PGC-1α Tfam、COX Ⅳ蛋白表达。
结果：
1.不同组别血清TNF-α的水平与对照组比较,模型组大鼠血清TNF-a明显升高,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组间无显著统计学差异,组间比较差异无统计学意义(P>0.05)。
2.不同组别骨骼肌TNF-α的水平与对照组比较,模型组大鼠骨骼肌TNFa明显升高,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR组骨骼肌TNFa明显低于白藜芦醇组,组间比较差异无统计学意义(P<0.05)。
3.不同组别骨骼肌AMPK mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌AMPK mRNA相对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(组间比较差异具有统计学意义P<0.01)。AICAR组AMPK mRNA相对含量明显高于白藜芦醇组,组间比较差异无统计学意义(P<0.01)。与对照组比较,模型组大鼠骨骼肌AMPK蛋白相对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高,组间比较差异具有统计学意义(P<0.01)。白藜芦醇组AMPK蛋白相对含量明显低于AICAR组,组间比较差异具有统计学意义(P<0.05)。
4.不同组别骨骼肌PGC-1a mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌PGC-1amRNA(?)目对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高,组间比较差异具有统计学意义(P<0.05)。AICAR组与白藜芦醇组间无明显统计学差异,组间比较差异无统计学意义(P>0.05)。与对照组比较,模型组大鼠骨骼肌PGCla蛋白相对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高,组间比较差异具有统计学意义(P<0.01)。白藜芦醇组PGC1a蛋白相对含量明显高于AICAR组,组间比较差异具有统计学意义(P<0.01)。
5.不同组别骨骼肌NRF-1mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌NRF1mRNA明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.05)。AICAR组与白藜芦醇组间无明显统计学差异(P>0.05)。与对照组比较,模型组大鼠骨骼肌NRF1蛋白明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.01)。白藜芦醇组NRF1蛋白明显高于AICAR组(P<0.01)。
6.不同组别骨骼肌Tfam mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌Tfam mRNA明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.05,P<0.01)。AICAR组与白藜芦醇组间无明显统计学差异(P>0.05)。与对照组比较,模型组大鼠骨骼肌Tfam蛋白明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.01)。白藜芦醇组Tfam蛋白明显高于AICAR组(P<0.01)。7.不同组别骨骼肌COX Ⅳ mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌COXIVmRNA明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.05)。AICAR组与白藜芦醇组间无明显统计学差异(P>0.05)。与对照组比较,模型组大鼠骨骼肌COX Ⅳ蛋白明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.01)。白藜芦醇组COX Ⅳ蛋白明显高于AICAR组(P<0.01)。
8.相关性分析骨骼肌TNF-a和AMPK呈负相关关系(R=-0.454,P<0.01)。骨骼肌PGC-1a mRNA和AMPKmRNA呈正相关关系(R=0.278,P<0.05)。骨骼肌TNF-a和PGC-1amRNA呈负相关关系(R=-0.780,P<0.01)。骨骼肌PGC-1a mRNA和NRFmRNA呈正相关关系(R=0.685,P<0.01)。骨骼肌PGC-1a mRNA和Tfam mRNA呈正相关关系(R=0.800,P<0.01)。
结论：
1. COPD大鼠骨骼肌存在TNF-α介导的炎症。
2. COPD大鼠骨骼肌AMPK水平下降,PGC-1α表达下降影响骨骼肌线粒体生物合成。
3. AMPK激动剂AICAR及白藜芦醇可通过活化AMPK,提高PGC-1α表达水平,改善了COPD运动性骨骼肌线粒体生物合成。
Part one
Background and objective
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation in the airways. Inflammatory responses are responsible for both the persistence of airflow limitation and also, the systemic effect involving multiple organ damage. Multiple studies have revealed recently that skeletal muscle dysfunction contributes in motionlessness in COPD patients, which has emerged as an important predictor for mortality in patients with severe COPD.
The mechanisms underlying skeletal muscle dysfunction in COPD is complicated. However, the presence of systemic inflammation in COPD patients has been widely accepted, that inflammation potentially initiates skeletal muscle damage in COPD patients. Tumor necrosis factor-a (TNF-a) has been shown as an important inflammatory mediator involved in the inflammatory process of COPD.
Mitochondria is the site where reactive oxygen species (ROS) and energy required for skeletal muscle movement, as well as the central link in the apoptosis. Therefore, mitochondrial dysfunction has become a major focus in COPD with skeletal muscle dysfunction. A number of studies have reported that moderate to severe COPD patients are with exercise-associated skeletal muscle atrophy, decrease in the density and structural abnormality of skeletal mitochondria.
We resort to a COPD rat model to analyze the morphological and untrastructural changes (muscle fiber and mitochondria) in this study. Resveratrol or AMPK agonists was administrated with the COPD rat model, then seral and skeletal muscle TNF-a levels and skeletal muscle morphology were analyzed. This study may provide experimental evidences for enlightening the role of inflammatory injury in skeletal muscle dysfunction in COPD.
Methods
1. COPD rat model:COPD model was prepared by two doses of intratracheal lipopolysaccharide (LPS) injection and repeatedly smoke exposure.
2. Grouping:SD rats were randomized into the control group, the COPD model group, AICAR,(AMPK agonist) group and resveratrol group. The control group and model group were given saline, AICAR, Chenopodium quinoa resveratrol.
3. Lung function:rat lung function was determined by a small animal spirometer (Buxco, USA).
4. Lung and skeletal muscle pathology:Lung and skeletal muscle slices were prepared and stained by HE and Masson staining.The pathological and ultrastructural changes of the lung and skeletal muscle were observed under a optical microscope and a electron microscope, separately.
Results
1The behavioral changes:The model group and the treatment group have shown irritability, cough, shortness of breath, reduced food and water intake early in the experiment. However, such changes have not been observed in the control group. Weight changes was not statistically different among each group.
2Lung function changes:The PEF, VT and EF50value was significantly lower in the modeling group as compared with the control group (P<0.01, P<0.05and P<0.05, respectively). The PEF, VT and EF50values were significantly higher in the AICAR group and the resveratrol group than that in the model group (P<0.05and P<0.01, respectively). There was no statistically significant difference between the AICAR group and the resveratrol group in PEF, VT and EF50(P>0.05).
3Pathological changes in the lung:COPD modelling group showed extensive thickening and destruction of alveolar walls, rupture and integration of alveoli, small airway cilia loss, airspace narrowing, as well as small vessel wall thickening. Lungs from the AICAR group showed a moderate amount of inflammatory cell infiltration, destruction and integration of the alveolar septa and alveolar enlargement. Lung tissues from the resveratrol group showed moderate inflammatory infiltration, destruction of the alveolar septa, small airway cilia loss and airspace narrowing.
4Morphology of skeletal muscle cells:The COPD modelling group showed mild atrophy of skeletal muscle cells, while collagen deposition was significantly more abundant compared with that of the control group. The resveratrol group and the AICAR group showed less reduce collagen fiber deposition among skeletal muscle cells compared with the COPD modelling group. As observed on the transmission electron microscope, the triceps muscle from the modeling group has reduced number of mitochondria, swelling, water-based change and vacuolization, as well as endometrial cristae destruction. However, the triceps muscle from the resveratrol group and the AICAR group remained relatively intact, with preserved mitochondria structure, myofilament integrity and normal distribution of myofibrils.
Conclusion
1The COPD rat model could be successfully duplicated by twice intratracheal instillation of lipopolysaccharide (LPS) and repeatedly smoke exposure.
2Inflammation and mitochondrial damage are prominent in skeletal muscles from the rat COPD model.
3Both AICAR and resveratrol administration could allievated skeletal muscle inflammation and mitochondrial damage in COPD models.
Part two
Background and Objective
In recent years, significant skeletal muscle dysfunction has been observed in COPD patients with reduced motion capacity. The mechanisms underlying skeletal muscle dysfunction in COPD is sophisticated. However, the presence and role of systemic inflammation has been widely accepted, which is suggested to be the initial factor of skeletal muscle dysfunction in COPD patients. Among all the inflammatory mediators, tumor necrosis factor-a (TNF-a) has been widely accepted as an important mediator involving in the inflammatory process of COPD.
AMP-activated protein kinase (AMPK) is an important protein kinase in eukaryotic cells. The role of AMPK in cell energy metabolism is largely dependent on regulating the activity of metabolic enzymes. Various studies have revealed that AMPK downstream target proteins are involved in the regulation of energy metabolism. But till now, little is known about the exact role and mechanism of AMPK on the inflammation-mediated dysfunction of mitochondrial biosynthesis within skeletal muscles in COPD.
This study was to elucidate the impact of TNF-a on mitochondrial biogenesis in skeletal muscle of COPD rats. First, we analyzed the relationships between serum and muscular TNF-a level with genetic expressions of AMPK, PGC-la and mitochondrial biogenesis-associated genes. Next we explored the role of PGC-la on mitochondrial biogenesis via administration of AMPK agonists or resveratrol. The current study might provide rationales for novel treatments against skeletal muscle disorders in patients with COPD.
Methods
1. Preparation and randomization of the rat COPD model:the rat COPD model was prepared in a way identical to that referred to in Part One of this thesis. SD rats were randomized as the control group, the COPD model group, the AICAR group,(AMPK agonist) group and the resveratrol group. The control group and model group were treated with saline, while rats in the AICAR group received Chenopodium or resveratrol.
2. Material processing and detection:The level of TNF-a was detected by enzyme-linked immunosorbent assay (ELISA) with serum samples or supernatants originated from triceps muscle homogenate. The expression of AMPK, NRF-1, PGC-la, Tfam and COX IV mRNA was analyzed by qPCR, while the expression of their protein countparts were measured by Western blot.
Results
1Serum TNF-a level:Serum TNF-a level was significantly higher in the COPD model group as compared with the control group (P<0.01). Serum TNF-a levels were significantly lower in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between serum TNF-a level in the AICAR group and the resveratrol group (P>0.05).
2The TNF-a levels in skeletal muscle:Muscle TNF-a level was significantly elevated in the COPD model group as compared with the control group (P<0.01). Muscle TNF-a levels were significantly lower in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle TNF-a level in the AICAR group and the resveratrol group (P>0.05).
3AMPK mRNA and protein expression in skeletal muscle:The expression of muscle AMPK mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle AMPK mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle AMPK mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of AMPK protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
4PGC-la mRNA and protein expression in skeletal muscle:The expression of muscle PGC-la mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle PGC-la mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle PGC-la mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of PGC-la protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
5NRF-1mRNA and protein expression in skeletal muscle:The expression of muscle NRF-1mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle NRF-1mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle NRF-1mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of NRF-1protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
6Tfam mRNA and protein expression in skeletal muscle:The expression of muscle Tfam mRNA and protein was significantly decreased in the COPD model group as compared with the control group (.P<0.01). The expression of muscle Tfam mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle Tfam mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of Tfam protein was significantly increased in the resveratrol group as compared with the AICAR group (P<0.05).
7COX IV mRNA and protein expression in skeletal muscle:The expression of muscle COX IV mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle COX IV mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle COX IV mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of COX Ⅳ protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
8Analysis of Correlations:The muscle TNF-a and AMPK level was negatively correlated (R=-0.454, P<0.01).Positive correlations were observed between the skeletal muscle PGC-1a mRNA and AMPKmRNA (R=0.278, P<0.05), skeletal muscle TNF-a and PGC-1a mRNA was negatively correlated (R=-0.780, P<0.01), skeletal muscle PGC-1a mRNA and NRF mRNA was positive correlations (R=0.685,P<0.01), and between skeletal muscle PGC-1a mRNA and Tfam mRNA was positive correlations (R=0.800, P<0.01).
Conclusion
1TNF-α mediated inflammation of skeletal muscle of COPD.
2The down-regulation of AMPK and PGC-1α are associated with the breakdown of mitochondrial biogenesis in skeletal muscle cells from the rat model of COPD.
3AMPK agonists and resveratrol are able to improve skeletal muscle mitochondrial biogenesis in COPD rats by activating the expression of AMPK and PGC-1α.
背景和目的：
慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)是一种以气流受限为特征的慢性气道疾病,同时也是一种涉及多器官受损的全身疾病。近年来国内外研究发现,部分运动受限的COPD患者表现为明显的骨骼肌功能障碍。对中、重度COPD患者,骨骼肌的消耗成为预计患者病死率的重要指标之一。
COPD的骨骼肌功能障碍形成机制复杂,系统性炎症在COPD患者中的存在已被广泛接受,有人认为炎症是COPD患者骨骼肌功能障碍的始动因素。其中肿瘤坏死因子-α(Tumor necrosis factor-a, TNF-a)作为一种重要炎症介质已被证明参与了COPD的炎症过程。
线粒体是骨骼肌运动所需能量的生成场所,也是活性氧(ROS)产生的主要场所,同时也处于细胞凋亡的中心环节。因此,线粒体功能障碍在COPD的骨骼肌功能障碍中越来越受到重视。已有研究发现,中重度COPD患者出现运动性骨骼肌萎缩、骨骼肌线粒体密度减少及结构异常。
我们拟通过建立COPD大鼠模型,观察COPD模型大鼠骨骼肌形态学变化及电镜下骨骼肌纤维与线粒体变化,同时给予白藜芦醇及AMP激活的蛋白激酶(Adenosine5'-monophosphate (AMP)-activated protein kinase, AMPK)激动剂干预。评估外周血及骨骼肌TNF-a水平与骨骼肌与线粒体的结构形态改变的关系,为炎症在COPD骨骼肌功能障碍中的损伤作用机制提供实验依据。
方法：
1.COPD大鼠模型制备用两次气管内注入脂多糖(LPS)和反复烟熏的方法制作COPD大鼠模型。
2.分组与处理雄性SD大鼠随机分为对照组、COPD模型组、AICAR (AMPK特异性激动剂)组和白藜芦醇组,对照组和模型组分别给予生理盐水、AICAR、白藜芦醇。
3.肺功能采用无束缚小动物肺功能仪(Buxco, USA)测定大鼠肺功能变化。
4.肺和骨骼肌病理采用HE、Masson染色光学显微镜下观察各组肺脏和骨骼肌的病理变化。及电镜观察骨骼肌与线粒体的超微结构改变。
结果：
1.各实验组大鼠行为变化模型组及各治疗组大鼠早期出现躁动不安、咳嗽、气急、、进食进水量逐渐减少等表现。正常对照组则始终未见上述表现。各组体重改变差异无显著性。
2.各实验组大鼠肺功能变化与对照组比较,模型组大鼠PEF明显降低(P<0.01),VT明显降低(P<0.05),EF50明显降低(P<0.05)。AICAR和白藜芦醇组PEF、均较模型组明显升高(P<0.05,P<0.01)。AICAR和白藜芦醇组VT均较模型组明显升高、EF50(P<0.05)。AICAR和白藜芦醇组EF50均较模型组明显升高(P<0.05)AICAR和白藜芦醇组间比较差异无统计学意义(P>0.05)。
3.大鼠肺组织病理变化COPD模型组可见广泛肺泡壁增厚、破坏,肺泡破裂、融合,小气道纤毛脱落,气腔狭窄,小血管壁增厚。AICAR组肺组织可见中量炎症细胞浸润,肺泡壁破坏、肺泡融合,肺泡腔增大；白藜芦醇组肺组织可见中量炎症细胞浸润,肺泡壁破坏、小气道纤毛脱落,气腔狭窄。
4.骨骼肌细胞形态学观察COPD模型组大鼠骨骼肌细胞轻度萎缩,胶原纤维沉积较对照组明显增多。白藜芦醇和AICAR组大鼠组骨骼肌细胞较COPD模型组大鼠胶原纤维沉积减少。透射电镜下观察显示：模型组大鼠的小腿三头肌线粒体减少,出现肿胀,水性变及空泡化,内膜、嵴破坏溶解改变；白藜芦醇组及AICAR组大鼠的小腿三头肌线粒体结构尚完整,肌丝完整,肌原纤维排列整齐,分布正常。
结论：
1.两次气管内注入脂多糖(LPS)和反复烟熏的方法可成功制作COPD大鼠模型。
2. COPD模型大鼠骨骼肌存在骨骼肌炎症及线粒体损伤。
3. AICAR及白藜芦醇可以改善COPD模型大鼠骨骼肌炎症反应,减轻线粒体结构损伤。
第二部分AMPK对COPD大鼠骨骼肌线粒体合成调控中的作用及白藜芦醇作用机制探讨
背景和目的：
近年来国内外研究发现,部分运动受限的COPD患者表现为明显的骨骼肌功能障碍。COPD的骨骼肌功能障碍形成机制复杂,系统性炎症在COPD患者中的存在已被广泛接受,TNF-α作为一种重要炎症介质已被证明参与了COPD的炎症过程。
AMPK作为真核生物细胞中一个重要的蛋白激酶,参与细胞的能量代谢过程,其通过调控代谢相关酶起作用。国内外研究发现AMPK的下游靶蛋白参与能量代谢调节有关。但是AMPK是否参与炎症介导的COPD骨骼肌线粒体生物合成障碍目前一无所知。
本研究拟通过观察大鼠外周血与骨骼肌TNF-α水平、骨骼肌AMPK表达、PGC-1α及线粒体生物合成相关基因表达的变化,进而探讨炎症状态下COPD模型大鼠骨骼肌线粒体合成的的影响,同时给予AMPK激动剂及白藜芦醇干预后观察PGC-1α变化及对骨骼肌线粒体生物合成的影响,为治疗COPD骨骼肌障碍提供新的理论基础。
方法：
1. COPD大鼠模型制备与分组与处理同第一部分。
2.取材与处理采用酶联免疫吸附(ELISA)法测定血清TNF-a浓度；小腿三头肌留取组织匀浆,取上清液采用ELISA法检测TNF-a浓度；采用荧光定量PCR分析检测AMPK、NRF-1、PGC-1α、Tfam、COX ⅣmRNA表达；采用Western blotting检测AMPK, TNF-α PGC-1α Tfam、COX Ⅳ蛋白表达。
结果：
1.不同组别血清TNF-α的水平与对照组比较,模型组大鼠血清TNF-a明显升高,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组间无显著统计学差异,组间比较差异无统计学意义(P>0.05)。
2.不同组别骨骼肌TNF-α的水平与对照组比较,模型组大鼠骨骼肌TNFa明显升高,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR组骨骼肌TNFa明显低于白藜芦醇组,组间比较差异无统计学意义(P<0.05)。
3.不同组别骨骼肌AMPK mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌AMPK mRNA相对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(组间比较差异具有统计学意义P<0.01)。AICAR组AMPK mRNA相对含量明显高于白藜芦醇组,组间比较差异无统计学意义(P<0.01)。与对照组比较,模型组大鼠骨骼肌AMPK蛋白相对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高,组间比较差异具有统计学意义(P<0.01)。白藜芦醇组AMPK蛋白相对含量明显低于AICAR组,组间比较差异具有统计学意义(P<0.05)。
4.不同组别骨骼肌PGC-1a mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌PGC-1amRNA(?)目对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高,组间比较差异具有统计学意义(P<0.05)。AICAR组与白藜芦醇组间无明显统计学差异,组间比较差异无统计学意义(P>0.05)。与对照组比较,模型组大鼠骨骼肌PGCla蛋白相对含量明显降低,组间比较差异具有统计学意义(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高,组间比较差异具有统计学意义(P<0.01)。白藜芦醇组PGC1a蛋白相对含量明显高于AICAR组,组间比较差异具有统计学意义(P<0.01)。
5.不同组别骨骼肌NRF-1mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌NRF1mRNA明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.05)。AICAR组与白藜芦醇组间无明显统计学差异(P>0.05)。与对照组比较,模型组大鼠骨骼肌NRF1蛋白明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.01)。白藜芦醇组NRF1蛋白明显高于AICAR组(P<0.01)。
6.不同组别骨骼肌Tfam mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌Tfam mRNA明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.05,P<0.01)。AICAR组与白藜芦醇组间无明显统计学差异(P>0.05)。与对照组比较,模型组大鼠骨骼肌Tfam蛋白明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.01)。白藜芦醇组Tfam蛋白明显高于AICAR组(P<0.01)。7.不同组别骨骼肌COX Ⅳ mRNA及蛋白表达的变化与对照组比较,模型组大鼠骨骼肌COXIVmRNA明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.05)。AICAR组与白藜芦醇组间无明显统计学差异(P>0.05)。与对照组比较,模型组大鼠骨骼肌COX Ⅳ蛋白明显降低(P<0.01)。AICAR和白藜芦醇组均较模型组明显升高(P<0.01)。白藜芦醇组COX Ⅳ蛋白明显高于AICAR组(P<0.01)。
8.相关性分析骨骼肌TNF-a和AMPK呈负相关关系(R=-0.454,P<0.01)。骨骼肌PGC-1a mRNA和AMPKmRNA呈正相关关系(R=0.278,P<0.05)。骨骼肌TNF-a和PGC-1amRNA呈负相关关系(R=-0.780,P<0.01)。骨骼肌PGC-1a mRNA和NRFmRNA呈正相关关系(R=0.685,P<0.01)。骨骼肌PGC-1a mRNA和Tfam mRNA呈正相关关系(R=0.800,P<0.01)。
结论：
1. COPD大鼠骨骼肌存在TNF-α介导的炎症。
2. COPD大鼠骨骼肌AMPK水平下降,PGC-1α表达下降影响骨骼肌线粒体生物合成。
3. AMPK激动剂AICAR及白藜芦醇可通过活化AMPK,提高PGC-1α表达水平,改善了COPD运动性骨骼肌线粒体生物合成。
Part one
Background and objective
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation in the airways. Inflammatory responses are responsible for both the persistence of airflow limitation and also, the systemic effect involving multiple organ damage. Multiple studies have revealed recently that skeletal muscle dysfunction contributes in motionlessness in COPD patients, which has emerged as an important predictor for mortality in patients with severe COPD.
The mechanisms underlying skeletal muscle dysfunction in COPD is complicated. However, the presence of systemic inflammation in COPD patients has been widely accepted, that inflammation potentially initiates skeletal muscle damage in COPD patients. Tumor necrosis factor-a (TNF-a) has been shown as an important inflammatory mediator involved in the inflammatory process of COPD.
Mitochondria is the site where reactive oxygen species (ROS) and energy required for skeletal muscle movement, as well as the central link in the apoptosis. Therefore, mitochondrial dysfunction has become a major focus in COPD with skeletal muscle dysfunction. A number of studies have reported that moderate to severe COPD patients are with exercise-associated skeletal muscle atrophy, decrease in the density and structural abnormality of skeletal mitochondria.
We resort to a COPD rat model to analyze the morphological and untrastructural changes (muscle fiber and mitochondria) in this study. Resveratrol or AMPK agonists was administrated with the COPD rat model, then seral and skeletal muscle TNF-a levels and skeletal muscle morphology were analyzed. This study may provide experimental evidences for enlightening the role of inflammatory injury in skeletal muscle dysfunction in COPD.
Methods
1. COPD rat model:COPD model was prepared by two doses of intratracheal lipopolysaccharide (LPS) injection and repeatedly smoke exposure.
2. Grouping:SD rats were randomized into the control group, the COPD model group, AICAR,(AMPK agonist) group and resveratrol group. The control group and model group were given saline, AICAR, Chenopodium quinoa resveratrol.
3. Lung function:rat lung function was determined by a small animal spirometer (Buxco, USA).
4. Lung and skeletal muscle pathology:Lung and skeletal muscle slices were prepared and stained by HE and Masson staining.The pathological and ultrastructural changes of the lung and skeletal muscle were observed under a optical microscope and a electron microscope, separately.
Results
1The behavioral changes:The model group and the treatment group have shown irritability, cough, shortness of breath, reduced food and water intake early in the experiment. However, such changes have not been observed in the control group. Weight changes was not statistically different among each group.
2Lung function changes:The PEF, VT and EF50value was significantly lower in the modeling group as compared with the control group (P<0.01, P<0.05and P<0.05, respectively). The PEF, VT and EF50values were significantly higher in the AICAR group and the resveratrol group than that in the model group (P<0.05and P<0.01, respectively). There was no statistically significant difference between the AICAR group and the resveratrol group in PEF, VT and EF50(P>0.05).
3Pathological changes in the lung:COPD modelling group showed extensive thickening and destruction of alveolar walls, rupture and integration of alveoli, small airway cilia loss, airspace narrowing, as well as small vessel wall thickening. Lungs from the AICAR group showed a moderate amount of inflammatory cell infiltration, destruction and integration of the alveolar septa and alveolar enlargement. Lung tissues from the resveratrol group showed moderate inflammatory infiltration, destruction of the alveolar septa, small airway cilia loss and airspace narrowing.
4Morphology of skeletal muscle cells:The COPD modelling group showed mild atrophy of skeletal muscle cells, while collagen deposition was significantly more abundant compared with that of the control group. The resveratrol group and the AICAR group showed less reduce collagen fiber deposition among skeletal muscle cells compared with the COPD modelling group. As observed on the transmission electron microscope, the triceps muscle from the modeling group has reduced number of mitochondria, swelling, water-based change and vacuolization, as well as endometrial cristae destruction. However, the triceps muscle from the resveratrol group and the AICAR group remained relatively intact, with preserved mitochondria structure, myofilament integrity and normal distribution of myofibrils.
Conclusion
1The COPD rat model could be successfully duplicated by twice intratracheal instillation of lipopolysaccharide (LPS) and repeatedly smoke exposure.
2Inflammation and mitochondrial damage are prominent in skeletal muscles from the rat COPD model.
3Both AICAR and resveratrol administration could allievated skeletal muscle inflammation and mitochondrial damage in COPD models.
Part two
Background and Objective
In recent years, significant skeletal muscle dysfunction has been observed in COPD patients with reduced motion capacity. The mechanisms underlying skeletal muscle dysfunction in COPD is sophisticated. However, the presence and role of systemic inflammation has been widely accepted, which is suggested to be the initial factor of skeletal muscle dysfunction in COPD patients. Among all the inflammatory mediators, tumor necrosis factor-a (TNF-a) has been widely accepted as an important mediator involving in the inflammatory process of COPD.
AMP-activated protein kinase (AMPK) is an important protein kinase in eukaryotic cells. The role of AMPK in cell energy metabolism is largely dependent on regulating the activity of metabolic enzymes. Various studies have revealed that AMPK downstream target proteins are involved in the regulation of energy metabolism. But till now, little is known about the exact role and mechanism of AMPK on the inflammation-mediated dysfunction of mitochondrial biosynthesis within skeletal muscles in COPD.
This study was to elucidate the impact of TNF-a on mitochondrial biogenesis in skeletal muscle of COPD rats. First, we analyzed the relationships between serum and muscular TNF-a level with genetic expressions of AMPK, PGC-la and mitochondrial biogenesis-associated genes. Next we explored the role of PGC-la on mitochondrial biogenesis via administration of AMPK agonists or resveratrol. The current study might provide rationales for novel treatments against skeletal muscle disorders in patients with COPD.
Methods
1. Preparation and randomization of the rat COPD model:the rat COPD model was prepared in a way identical to that referred to in Part One of this thesis. SD rats were randomized as the control group, the COPD model group, the AICAR group,(AMPK agonist) group and the resveratrol group. The control group and model group were treated with saline, while rats in the AICAR group received Chenopodium or resveratrol.
2. Material processing and detection:The level of TNF-a was detected by enzyme-linked immunosorbent assay (ELISA) with serum samples or supernatants originated from triceps muscle homogenate. The expression of AMPK, NRF-1, PGC-la, Tfam and COX IV mRNA was analyzed by qPCR, while the expression of their protein countparts were measured by Western blot.
Results
1Serum TNF-a level:Serum TNF-a level was significantly higher in the COPD model group as compared with the control group (P<0.01). Serum TNF-a levels were significantly lower in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between serum TNF-a level in the AICAR group and the resveratrol group (P>0.05).
2The TNF-a levels in skeletal muscle:Muscle TNF-a level was significantly elevated in the COPD model group as compared with the control group (P<0.01). Muscle TNF-a levels were significantly lower in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle TNF-a level in the AICAR group and the resveratrol group (P>0.05).
3AMPK mRNA and protein expression in skeletal muscle:The expression of muscle AMPK mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle AMPK mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle AMPK mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of AMPK protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
4PGC-la mRNA and protein expression in skeletal muscle:The expression of muscle PGC-la mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle PGC-la mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle PGC-la mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of PGC-la protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
5NRF-1mRNA and protein expression in skeletal muscle:The expression of muscle NRF-1mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle NRF-1mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle NRF-1mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of NRF-1protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
6Tfam mRNA and protein expression in skeletal muscle:The expression of muscle Tfam mRNA and protein was significantly decreased in the COPD model group as compared with the control group (.P<0.01). The expression of muscle Tfam mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle Tfam mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of Tfam protein was significantly increased in the resveratrol group as compared with the AICAR group (P<0.05).
7COX IV mRNA and protein expression in skeletal muscle:The expression of muscle COX IV mRNA and protein was significantly decreased in the COPD model group as compared with the control group (P<0.01). The expression of muscle COX IV mRNA and protein was significantly higher in the AICAR group and the resveratrol group than that of the COPD model group (P<0.01in both situations). There was no statistically significant difference between muscle expression of muscle COX IV mRNA in the AICAR group and the resveratrol group (P>0.05). Muscle expression of COX Ⅳ protein was significantly decreased in the resveratrol group as compared with the AICAR group (P<0.05).
8Analysis of Correlations:The muscle TNF-a and AMPK level was negatively correlated (R=-0.454, P<0.01).Positive correlations were observed between the skeletal muscle PGC-1a mRNA and AMPKmRNA (R=0.278, P<0.05), skeletal muscle TNF-a and PGC-1a mRNA was negatively correlated (R=-0.780, P<0.01), skeletal muscle PGC-1a mRNA and NRF mRNA was positive correlations (R=0.685,P<0.01), and between skeletal muscle PGC-1a mRNA and Tfam mRNA was positive correlations (R=0.800, P<0.01).
Conclusion
1TNF-α mediated inflammation of skeletal muscle of COPD.
2The down-regulation of AMPK and PGC-1α are associated with the breakdown of mitochondrial biogenesis in skeletal muscle cells from the rat model of COPD.
3AMPK agonists and resveratrol are able to improve skeletal muscle mitochondrial biogenesis in COPD rats by activating the expression of AMPK and PGC-1α.
引文
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