Impaired PGC-1α function in muscle in Huntington's disease
Impaired PGC-1α function in muscle in Huntington's disease
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DOI：
10.1093/hmg/ddp243
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发表时间：
2009-08-15
影响因子：
3.5
通讯作者：
Beal, M. Flint
中科院分区：
文献类型：
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作者：
Chaturvedi, Rajnish K.;Adhihetty, Peter;Beal, M. Flint
我们研究了过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）在亨廷顿病（HD）肌肉功能障碍中的作用。我们观察到HD转基因小鼠肌肉中PGC-1 α和靶基因表达减少。我们通过给予分解代谢应激物β-胍基丙酸（GPA），一种降低ATP水平的肌酸类似物，激活AMP激活蛋白激酶（AMPK），进而激活PGC-1 α，在HD小鼠中产生慢性能量剥夺。GPA治疗导致野生型小鼠AMPK、PGC-1 α靶基因、氧化磷酸化基因、电子传递链和线粒体生物发生基因的表达增加，氧化肌纤维、线粒体数量和运动性能增加，但HD小鼠没有。在HD患者的肌肉活检中，PGC-1 α、PGC-1 β和氧化纤维减少。氧耗量，PGC-1 α，NRF 1和GPA反应显着降低成肌细胞从HD患者。敲低突变亨廷顿蛋白导致HD成肌细胞中PGC-1 α表达增加。最后，在HD小鼠中，腺病毒介导的PGC-1 α递送导致PGC-1 α和氧化肌纤维标记物的表达增加，并逆转GPA的钝化反应。这些发现表明，PGC-1 α的功能受损在HD的肌肉功能障碍中起着关键作用，并且用增强PGC-1 α功能的药物治疗可以发挥治疗益处。此外，肌肉可以提供容易接近的组织，在该组织中监测治疗干预。
We investigated the role of PPAR gamma coactivator 1 alpha (PGC-1 alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1 alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1 alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1 alpha target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice. In muscle biopsies from HD patients, there was decreased PGC-1 alpha, PGC-1 beta and oxidative fibers. Oxygen consumption, PGC-1 alpha, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1 alpha expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1 alpha resulted increased expression of PGC-1 alpha and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1 alpha plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1 alpha function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.