Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia
Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia
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DOI：
10.1096/fj.11-191262
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发表时间：
2011-12-01
期刊：
影响因子：
4.8
通讯作者：
Sonderegger, Peter
中科院分区：
文献类型：
--
作者：
Buetikofer, Lukas;Zurlinden, Andreas;Sonderegger, Peter
骨骼肌减少症的病因和发病机制，即随着年龄的增长骨骼肌质量和力量的逐渐下降，仍然知之甚少。我们最近发现，运动神经元中神经丝氨酸蛋白酶神经胰蛋白酶的过度表达会在几天内导致其神经肌肉接头（NMJ）变性。因此，我们想知道神经胰蛋白酶依赖性NMJ变性是否也影响骨骼肌的结构和功能。使用神经胰蛋白酶过度表达和神经胰蛋白酶缺乏小鼠的组织学和功能分析，我们发现，在运动神经元中神经胰蛋白酶的过度表达在年轻成年小鼠中安装了完整的肌肉减少症表型。特征性肌肉变化包括肌纤维数量减少、纤维厚度异质性增加、核更集中、纤维类型分组和I型纤维比例增加。与年龄依赖性肌减少症一样，NMJ的过度碎片伴随着肌肉变化。这些结果表明，在导致肌肉减少症的致病途径开始时，NMJ通过聚集蛋白的蛋白水解切割而不稳定。对神经胰蛋白酶缺乏和聚集蛋白过度表达小鼠的研究表明，老年肌肉减少症在没有神经胰蛋白酶的情况下也会发生，并且聚集蛋白水平升高也无法预防。我们的研究结果将神经胰蛋白酶和年龄依赖性肌肉减少症定义为2种病因不同实体的共同最终结局。布蒂克兰湖，1996年，博利格湾F.、Kunz，B.，Sonderegger，P.通过聚集蛋白的蛋白水解裂解引起的神经肌肉接头的不稳定导致早熟性肌肉减少症。FASEB J. 25，4378-4393（2011）。www.fasebj.org
Etiology and pathogenesis of sarcopenia, the progressive decline in skeletal muscle mass and strength that occurs with aging, are still poorly understood. We recently found that overexpression of the neural serine protease neurotrypsin in motoneurons resulted in the degeneration of their neuromuscular junctions (NMJ) within days. Therefore, we wondered whether neurotrypsin-dependent NMJ degeneration also affected the structure and function of the skeletal muscles. Using histological and functional analyses of neurotrypsin-overexpressing and neurotrypsin-deficient mice, we found that overexpression of neurotrypsin in motoneurons installed the full sarcopenia phenotype in young adult mice. Characteristic muscular alterations included a reduced number of muscle fibers, increased heterogeneity of fiber thickness, more centralized nuclei, fiber-type grouping, and an increased proportion of type I fibers. As in age-dependent sarcopenia, excessive fragmentation of the NMJ accompanied the muscular alterations. These results suggested the destabilization of the NMJ through proteolytic cleavage of agrin at the onset of a pathogenic pathway ending in sarcopenia. Studies of neurotrypsin-deficient and agrin-overexpressing mice revealed that old-age sarcopenia also develops without neurotrypsin and is not prevented by elevated levels of agrin. Our results define neurotrypsin-and age-dependent sarcopenia as the common final outcome of 2 etiologically distinct entities.-Butikofer, L., Zurlinden, A., Bolliger, M. F., Kunz, B., Sonderegger, P. Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia. FASEB J. 25, 4378-4393 (2011). www.fasebj.org