Age-Dependent Biochemical Dysfunction in Skeletal Muscle of Triple-Transgenic Mouse Model of Alzheimer's Disease
Age-Dependent Biochemical Dysfunction in Skeletal Muscle of Triple-Transgenic Mouse Model of Alzheimer's Disease
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DOI：
10.2174/1567205012666150204124852
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发表时间：
2015-01-01
影响因子：
2.1
通讯作者：
Videira, Romeu A.
中科院分区：
文献类型：
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作者：
Monteiro-Cardoso, Vera F.;Castro, Marisa;Videira, Romeu A.
阿尔茨海默病作为一种系统性病理学的出现，使研究范式转向更好地了解疾病的分子基础，同时考虑脑和外周组织的病理生理变化。在本研究中，我们评估了疾病进展对从3、6和12个月大的3xTg-AD小鼠（阿尔茨海默病模型）和相应年龄匹配的nonTg小鼠获得的骨骼肌生理相关特征的影响。我们的研究结果表明，骨骼肌功能已经在3个月大的3xTg-AD小鼠的乙酰胆碱酯酶和过氧化氢酶活性不足，以及线粒体膜的脂肪酸组成的改变证明了这一点。此外，淀粉样蛋白β（1-40）肽的年龄依赖性积累发生在骨骼肌的3xTg-AD小鼠，生物能量学线粒体功能障碍之前的影响，这是只在12个月大时检测到，其特征是呼吸控制比和ADP/O指数下降，并通过复合物I活性受损。HPLC-MS/MS分析显示，与年龄匹配的nonTg小鼠相比，12月龄的3xTg-AD小鼠骨骼肌组织的磷脂组成发生了显著变化。在3xTg-AD小鼠中检测到与含有花生四烯酸的磷脂酰胆碱分子种类减少相关的溶血磷脂酰胆碱水平增加，表明磷脂酶A（2）活性增强和骨骼肌炎症。此外，与年龄匹配的nonTg小鼠相比，在3xTg-AD小鼠中观察到磷脂酰乙醇胺缩醛磷脂含量减少和磷脂酰肌醇水平增加。总之，这些观察结果表明，3xTg-AD小鼠的骨骼肌更容易发生氧化和炎症事件。
The emergence of Alzheimer's disease as a systemic pathology shifted the research paradigm toward a better understanding of the molecular basis of the disease considering the pathophysiological changes in both brain and peripheral tissues. In the present study, we evaluated the impact of disease progression on physiological relevant features of skeletal muscle obtained from 3, 6 and 12 month-old 3xTg-AD mice, a model of Alzheimer's disease, and respective age-matched nonTg mice. Our results showed that skeletal muscle functionality is already affected in 3-month-old 3xTg-AD mice as evidenced by deficient acetylcholinesterase and catalase activities as well as by alterations in fatty acid composition of mitochondrial membranes. Additionally, an age-dependent accumulation of amyloid-beta(1-40) peptide occurred in skeletal muscle of 3xTg-AD mice, an effect that preceded bioenergetics mitochondrial dysfunction, which was only detected at 12 months of age, characterized by decreased respiratory control ratio and ADP/O index and by an impairment of complex I activity. HPLC-MS/MS analyses revealed significant changes in phospholipid composition of skeletal muscle tissues from 3xTg-AD mice with 12 months of age when compared with age-matched nonTg mice. Increased levels of lyso-phosphatidylcholine associated with a decrease of phosphatidylcholine molecular species containing arachidonic acid were detected in 3xTg-AD mice, indicating an enhancement of phospholipase A(2) activity and skeletal muscle inflammation. Additionally, a decrease of phosphatidylethanolamine plasmalogens content and an increase in phosphatidylinositol levels was observed in 3xTg-AD mice when compared with age-matched nonTg mice. Altogether, these observations suggest that the skeletal muscle of 3xTg-AD mice are more prone to oxidative and inflammatory events.