Department of Biomedical Sciences for Health, University of Milan, Segrate, Italy.
Antioxid Redox Signal. 2012 Nov 15;17(10):1333-50. doi: 10.1089/ars.2012.4524. Epub 2012 Jun 13.
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.
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.
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 γ co-activator 1α (PGC1α), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers.
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.
本研究利用蛋白质组学、生化和酶学测定以及生物信息学工具，对肌萎缩侧索硬化症（ALS）（SOD1(G93A)）小鼠模型后肢（比目鱼肌）和前肢（肱三头肌）肌肉中的蛋白质变化进行了特征描述。本研究旨在确定与疾病进展相关的关键分子特征。
两种肌肉类型都有共同的早期复合物 I 下调。在后肢，氧化代谢的早期增加与呼吸链解偶联、NADH/NAD(+) 失衡以及活性氧（ROS）产生增加有关。由于复合物 I 失活导致的 NADH 溢出会引起 TCA 通量紊乱，导致柠檬酸生成，触发脂肪酸合酶（FAS）和脂质过氧化。这些早期代谢变化在后肢中出现，随后是随着时间的推移持续且相对较高的代谢和细胞骨架紊乱，先于并可能促进该肌肉在晚期的进行性肌肉萎缩。相比之下，在前肢中，复合物 I 和 II 的早期下调与氧化代谢的减少有关，这促进了代谢稳态，同时伴随着更大的细胞骨架稳定反应。然而，这些早期的代偿系统在稍后的时间点会减弱。
在 ALS 模型中鉴定出潜在的早期和晚期疾病分子特征：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-激酶功能作为诊断标记物，过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC1α）、Sema-3A 和 Rho 相关蛋白激酶 1（ROCK1）发挥疾病进展标记物的作用。
后肢和前肢细胞代谢和细胞骨架紊乱的不同模式确定了与疾病进展相关的潜在代谢紊乱/代谢亢进分子特征，这些特征可能作为 ALS 患者的诊断/疾病进展标志物。
