Evidence for defective energy homeostasis in amyotrophic lateral sclerosis:: benefit of a high-energy diet in a transgenic mouse
Evidence for defective energy homeostasis in amyotrophic lateral sclerosis:: benefit of a high-energy diet in a transgenic mouse
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DOI：
10.1073/pnas.0402026101
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发表时间：
2004-07-27
影响因子：
11.1
通讯作者：
Loeffler, JP
中科院分区：
文献类型：
--
作者：
Dupuis, L;Oudart, H;Loeffler, JP
肌萎缩性侧索硬化症（ALS）是一种成人发病的神经退行性疾病，其特征是运动神经元的选择性丧失和进行性肌肉萎缩。越来越多的证据表明，线粒体功能障碍不仅发生在运动神经元中，也发生在骨骼肌中，可能在发病机制中起关键作用。在这方面，肌酸可以延长ALS G93A小鼠系的预期寿命，肌酸是一种改善肌肉功能的细胞内能量穿梭体。此外，散发性肌萎缩侧索硬化症患者群体表现出一种起源不明的全身性高代谢状态。总之，这些发现引导我们探索能量稳态的改变是否有助于疾病的进程。在这里，我们展示了转基因ALS小鼠中一些代谢指标的重要变化，这些指标都显示出代谢缺陷。这些改变在疾病无症状期早期伴随着脂肪组织积累减少、能量消耗增加和伴随的骨骼肌高代谢。用高能量饮食来弥补这种能量失衡，使平均存活率提高了20%。综上所述，我们认为主要由肌肉引起的高代谢本身可能是运动神经元易损性增加的一种额外驱动力。
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.