Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging.
Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging.
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DOI：
10.1016/j.celrep.2014.07.061
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发表时间：
2014-09-11
期刊：
影响因子：
8.8
通讯作者：
Sandri M
中科院分区：
文献类型：
--
作者：
Carnio S;LoVerso F;Baraibar MA;Longa E;Khan MM;Maffei M;Reischl M;Canepari M;Loefler S;Kern H;Blaauw B;Friguet B;Bottinelli R;Rudolf R;Sandri M
与年龄相关的组织退化的细胞基础在很大程度上仍然不清楚。激活补偿机制以响应环境应激的能力是细胞功能存活和维持的重要因素。自噬在短期和长期应激下都被激活，并且需要清除细胞中功能失调的细胞器和改变的蛋白质。我们报告说，肌肉中的特定自噬抑制对神经肌肉突触功能有重大影响，因此，对肌肉力量，最终影响动物的寿命。自噬的抑制也加剧了肌肉中的衰老表型，如线粒体功能障碍、氧化应激和严重虚弱。线粒体功能障碍和氧化应激直接影响肌动蛋白-肌球蛋白相互作用和力的产生，但对神经肌肉突触的稳定性影响有限。这些结果表明，与年龄相关的突触结构和功能的退化是由缺陷的自噬加剧。肌肉中的自噬随着年龄的增长而减少，并且救援可以防止肌肉损失肌肉中的自噬抑制缩短动物的寿命自噬是维持正常的肌肉-神经相互作用所必需的自噬损伤诱导收缩蛋白的氧化，导致虚弱与年龄相关的组织退化的细胞基础在很大程度上仍然不清楚。自噬通常在应激条件下被激活，并随着年龄的增长而下降。Carnio等人现在报道，肌肉中特异性自噬抑制对神经肌肉突触功能有重大影响，因此对肌肉力量有重大影响，最终影响动物的寿命。自噬抑制也加剧了几种衰老表型，证实了自噬是健康衰老所必需的。
The cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy. Autophagy in muscle decreases with age, and rescue prevents muscle loss Autophagy inhibition in muscles shortens animal lifespan Autophagy is required to maintain a normal muscle-nerve interaction Autophagy impairment induces oxidation of contractile proteins, causing weakness The cellular basis of age-related tissue deterioration remains largely obscure. Autophagy is often activated under stress conditions and declines with age. Carnio et al. now report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and consequently on muscle strength, ultimately affecting the lifespan of animals. Autophagy inhibition also exacerbates several aging phenotypes, confirming that autophagy is required for healthy aging.