Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans
Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans
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DOI：
10.18632/aging.101141
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发表时间：
2016-12-01
期刊：
影响因子：
5.2
通讯作者：
Dennis, Richard A.
中科院分区：
文献类型：
--
作者：
Ayyadevara, Srinivas;Balasubramaniam, Meenakshisundaram;Dennis, Richard A.
在正常组织中，蛋白质聚集随着年龄的增加而增加，在阿尔茨海默病患者的海马体和小鼠心肌中，蛋白质聚集随着病理和年龄的增加而增加。我们现在的问题是，人类骨骼肌是否随着年龄的增长而积累聚集。从5名年轻人(23-27岁)和5名老年人(-80岁)的股外侧肌活检组织中分离出洗涤剂不溶蛋白聚集体。当从年长的受试者中分离出来时，凝胶电泳后的聚集体含有的蛋白质是年轻人的2.1%(P<；0.0001)。在515种蛋白质中，56种(11%)在老年肌肉中含量显著增加，而21种(4%)随着年龄的增长而减少(各P<；0.05)。然后，通过RNA干扰将其中七种蛋白质的同源基因定位于线虫。在7个击倒处理中，有6个降低了老年线虫的蛋白质聚集(6-45%，P<；0.01至0.0001)和增加肌肉质量(1.5-1.85倍，P<；0.01至0.0001)，并在线虫淀粉样病模型中挽救了活动度(1.4-1.65倍，P=0.0005)。我们得出结论，在老化的人类肌肉中发现的差异丰富的特定聚集蛋白，具有在功能上促进线虫聚集和与年龄相关的肌肉损失的同源蛋白，因此可以被认为是治疗人类骨骼减少症的潜在药物靶点。
Protein aggregation increases with age in normal tissues, and with pathology and age in Alzheimer's hippocampus and mouse cardiac muscle. We now ask whether human skeletal muscle accumulates aggregates with age. Detergent-insoluble protein aggregates were isolated from vastus lateralis biopsies from 5 young (23-27 years of age) and 5 older (64-80 years) adults. Aggregates, quantified after gel electrophoresis, contain 2.1-fold more protein (P< 0.0001) when isolated from older subjects relative to young. Of 515 proteins identified by liquid chromatography coupled to tandem mass spectrometry, 56 (11%) were significantly more abundant in older muscle, while 21 (4%) were depleted with age (each P< 0.05). Orthologs to seven of these proteins were then targeted in C. elegans by RNA interference. Six of the seven knockdown treatments decreased protein aggregation (range 6-45%, P< 0.01 to < 0.0001) and increased muscle mass (range 1.5-to 1.85fold, P< 0.01 to < 0.0001) in aged nematodes, and rescued mobility (range 1.4 to 1.65-fold, P= 0.0005 each) in a nematode amyloidopathy model. We conclude that specific aggregate proteins, discovered as differentially abundant in aging human muscle, have orthologs that contribute functionally to aggregation and age-associated muscle loss in nematodes, and thus can be considered potential drug targets for sarcopenia in humans.