Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1G93A Mouse Model
Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1G93A Mouse Model
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DOI：
10.1089/ars.2012.4524
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发表时间：
2012-11-01
影响因子：
6.6
通讯作者：
Gelfi, Cecilia
中科院分区：
文献类型：
--
作者：
Capitanio, Daniele;Vasso, Michele;Gelfi, Cecilia
目的：本研究利用蛋白质组学、生物化学和酶测定以及生物信息学工具来表征肌萎缩侧索硬化（ALS）（SOD1（G93A））小鼠模型中后肢（腓肠肌）和前肢（三头肌）肌肉中的蛋白质改变。本研究的目的是确定参与疾病进展的关键分子特征。结果：两种肌肉类型的共同点是复合物I的早期下调。在后肢，氧化代谢的早期增加与呼吸链解偶联、NADH/NAD（+）失衡和活性氧（ROS）产生增加有关。由于复合物I失活引起的NADH溢出诱导TCA通量扰动，导致柠檬酸盐产生，触发脂肪酸合酶（FAS）和脂质过氧化。这些早期的代谢变化，在后肢随后持续和相对较高的代谢和细胞骨架紊乱随着时间的推移之前，并可能催化进行性肌肉萎缩在这个肌肉在后期阶段。相比之下，在前肢，有一个早期下调的复合物I和II，这是与减少氧化代谢，促进代谢稳态，伴随着更大的细胞骨架稳定反应。然而，这些早期的补偿系统在稍后的时间点减少。创新：ALS模型中潜在早期和晚期疾病分子特征的鉴定：肌肉白蛋白、复合物I、复合物II、柠檬酸合酶、FAS和磷酸肌醇3-激酶作为诊断标志物发挥作用，过氧化物酶体增殖物激活受体γ共激活因子1 α（PGC1 α）、Sema-3A和Rho相关蛋白激酶1（ROCK 1）作为疾病进展标志物发挥作用。结论：后肢和前肢中细胞代谢和细胞骨架紊乱的不同模式识别了与疾病进展相关的潜在代谢异常/高代谢分子特征，其可作为ALS患者的诊断/疾病进展标志物。抗氧化剂。氧化还原信号。17，1333 - 1350.
Aims: This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1(G93A)) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. Results: Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD(+), and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. Innovation: The identification of potential early-and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1 alpha), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. Conclusion: The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALS patients. Antioxid. Redox Signal. 17, 1333-1350.