Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560 029, India.
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560 029, India.
Dis Model Mech. 2018 Apr 16;11(4):dmm031997. doi: 10.1242/dmm.031997.
Skeletal muscle atrophy is the most prominent feature of amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease of motor neurons. However, the contribution of skeletal muscle to disease progression remains elusive. Our previous studies have shown that intrathecal injection of cerebrospinal fluid from sporadic ALS patients (ALS-CSF) induces several degenerative changes in motor neurons and glia of neonatal rats. Here, we describe various pathologic events in the rat extensor digitorum longus muscle following intrathecal injection of ALS-CSF. Adenosine triphosphatase staining and electron microscopic (EM) analysis revealed significant atrophy and grouping of type 2 fibres in ALS-CSF-injected rats. Profound neuromuscular junction (NMJ) damage, such as fragmentation accompanied by denervation, were revealed by α-bungarotoxin immunostaining. Altered expression of key NMJ proteins, rapsyn and calpain, was also observed by immunoblotting. In addition, EM analysis showed sarcolemmal folding, Z-line streaming, structural alterations of mitochondria and dilated sarcoplasmic reticulum. The expression of trophic factors was affected, with significant downregulation of vascular endothelial growth factor (VEGF), marginal reduction in insulin-like growth factor-1 (IGF-1), and upregulation of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). However, motor neurons might be unable to harness the enhanced levels of BDNF and GDNF, owing to impaired NMJs. We propose that ALS-CSF triggers motor neuronal degeneration, resulting in pathological changes in the skeletal muscle. Muscle damage further aggravates the motor neuronal pathology, because of the interdependency between them. This sets in a vicious cycle, leading to rapid and progressive loss of motor neurons, which could explain the relentless course of ALS.This article has an associated First Person interview with the first author of the paper.
骨骼肌萎缩是肌萎缩侧索硬化症（ALS）的最显著特征，ALS 是一种成年起病的运动神经元退行性疾病。然而，骨骼肌对疾病进展的贡献仍不清楚。我们之前的研究表明，鞘内注射散发性 ALS 患者的脑脊液（ALS-CSF）可诱导新生大鼠运动神经元和神经胶质发生几种退行性变化。在这里，我们描述了鞘内注射 ALS-CSF 后大鼠伸趾长肌中的各种病理事件。三磷酸腺苷染色和电子显微镜（EM）分析显示，ALS-CSF 注射大鼠的 2 型纤维明显萎缩和聚集。α-银环蛇毒素免疫染色显示神经肌肉接头（NMJ）严重损伤，如伴有去神经支配的碎片化。免疫印迹还观察到关键 NMJ 蛋白rapsyn 和钙蛋白酶的表达改变。此外，EM 分析显示肌膜折叠、Z 线流、线粒体结构改变和扩张的肌浆网。营养因子的表达受到影响，血管内皮生长因子（VEGF）显著下调，胰岛素样生长因子-1（IGF-1）略有减少，脑源性神经营养因子（BDNF）和胶质源性神经营养因子（GDNF）上调。然而，由于 NMJ 受损，运动神经元可能无法利用增强的 BDNF 和 GDNF 水平。我们提出，ALS-CSF 触发运动神经元变性，导致骨骼肌发生病理变化。肌肉损伤进一步加重运动神经元病理学，因为它们相互依存。这就形成了一个恶性循环，导致运动神经元迅速而进行性丧失，这可以解释 ALS 的无情进程。本文附有该论文第一作者的第一人称采访。
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