Suppressed autophagy flux in skeletal muscle of an amyotrophic lateral sclerosis mouse model during disease progression.
Suppressed autophagy flux in skeletal muscle of an amyotrophic lateral sclerosis mouse model during disease progression.
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DOI：
10.14814/phy2.12271
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发表时间：
2015-01-01
影响因子：
2.5
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Xiao Y;Ma C;Yi J;Wu S;Luo G;Xu X;Lin PH;Sun J;Zhou J
肌萎缩侧索硬化（ALS）运动神经元变性与异常蛋白内含物的积累有关。自噬是一种以错误折叠的蛋白质和受损细胞器为目标进行溶酶体降解的细胞内过程，在生存和疾病状态中起着至关重要的作用。研究了自噬在运动神经元退行性变中的作用，并将运动神经元自噬作为ALS治疗的靶点。然而，结果是相当矛盾的。其他细胞类型中可能存在的自噬缺陷也可能使结果复杂化。在这里，我们研究了ALS小鼠模型G93 A骨骼肌中的自噬活性。通过过表达荧光蛋白LC 3-RFP，我们发现当小鼠正常饮食时，疾病进展期间G93 A肌肉中自噬体形成的基础增加。正如预期的那样，自噬诱导程序（饥饿加秋水仙碱）增强了正常小鼠骨骼肌中的自噬通量。然而，响应于相同的自噬诱导程序，G93 A肌肉显示出自噬通量的显著减少。免疫印迹分析显示，与细胞凋亡相关的切割caspase-3的增加与参与自噬的几种关键蛋白的切割有关，包括Beclin-1，这是连接自噬和细胞凋亡途径的重要分子。综上所述，我们提供的证据表明，细胞保护性自噬途径在G93 A骨骼肌中受到抑制，这种抑制可能与ALS进展过程中细胞凋亡的增强有关。骨骼肌中的异常自噬活性可能有助于ALS中的肌肉变性和疾病进展。肌萎缩侧索硬化症（ALS）是一种胎儿神经肌肉疾病，其中骨骼肌受到实质性影响。这项研究发现了骨骼肌中自噬通路的特定缺陷，这可能在ALS疾病进展中起重要作用。
Accumulation of abnormal protein inclusions is implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Autophagy, an intracellular process targeting misfolded proteins and damaged organelles for lysosomal degradation, plays crucial roles in survival and diseased conditions. Efforts were made to understand the role of autophagy in motor neuron degeneration and to target autophagy in motor neuron for ALS treatment. However, results were quite contradictory. Possible autophagy defects in other cell types may also complicate the results. Here, we examined autophagy activity in skeletal muscle of an ALS mouse model G93A. Through overexpression of a fluorescent protein LC3‐RFP, we found a basal increase in autophagosome formation in G93A muscle during disease progression when the mice were on a regular diet. As expected, an autophagy induction procedure (starvation plus colchicine) enhanced autophagy flux in skeletal muscle of normal mice. However, in response to the same autophagy induction procedure, G93A muscle showed significant reduction in the autophagy flux. Immunoblot analysis revealed that increased cleaved caspase‐3 associated with apoptosis was linked to the cleavage of several key proteins involved in autophagy, including Beclin‐1, which is an essential molecule connecting autophagy and apoptosis pathways. Taking together, we provide the evidence that the cytoprotective autophagy pathway is suppressed in G93A skeletal muscle and this suppression may link to the enhanced apoptosis during ALS progression. The abnormal autophagy activity in skeletal muscle likely contributes muscle degeneration and disease progression in ALS. Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disease, in which skeletal muscle is substantially affected. This study discovered a specific defect in autophagy pathway in skeletal muscle, which likely plays an important role in ALS disease progression.