Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients
Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients
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DOI：
10.1016/j.exger.2012.03.002
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发表时间：
2013-01-01
影响因子：
3.9
通讯作者：
Vrijbloed, Jan Willem
中科院分区：
文献类型：
--
作者：
Hettwer, Stefan;Dahinden, Pius;Vrijbloed, Jan Willem
骨骼肌减少症是最近定义的一种医学疾病，描述为与年龄相关的骨骼肌质量和功能的丧失。最近，一种转基因小鼠模型被描述为将农业蛋白降解升高引起的神经肌肉连接处的分散与肌肉减少症的快速发作联系起来。与野生鼠相比，这些小鼠的血清c端agrin片段（CAF）水平显著升高。设计了一系列的实验，以确定在人类肌肉减少症的发展中，农业蛋白降解升高的意义。建立了Western blot定量检测人血清CAF的方法。第一项针对自愿献血者的试验（n=169，年龄19-74岁）检测到CAF在2.76 +/- 0.95 ng/ml的有限范围内。在肌肉减少症患者（根据临床和仪器标准诊断）中，与年龄匹配的对照组相比，平均CAF水平显著升高（p=9.8E10-9; n=73；年龄65-87岁）。在所有肌肉减少症患者中，与对照组相比，40%的患者CAF水平升高，且不重叠。有证据表明，在肌少症患者的一个相当大的子集中，agrin/神经胰蛋白酶系统的致病作用。与年龄匹配的健康志愿者相比，这些患者的特点是血液中CAF水平升高，这表明确定了一种依赖于谷物的肌肉减少症。在大量肌少症患者亚群中，CAF水平升高表明存在一种特殊形式的肌少症，CAF可能成为一种生物标志物和治疗干预的新靶点。这种方法的可行性是通过开发一种能够在体外和体内抑制神经胰蛋白酶的小分子来证明的。(C) 2012爱思唯尔公司版权所有。
Sarcopenia is a recently defined medical condition described as age-associated loss of skeletal muscle mass and function. Recently, a transgenic mouse model was described linking dispersal of the neuromuscular junction caused by elevated agrin degradation to the rapid onset of sarcopenia. These mice show a significant elevation of serum levels of a C-terminal agrin fragment (CAF) compared to wild-type littermates. A series of experiments was designed to ascertain the significance of elevated agrin degradation in the development of human sarcopenia. A quantitative Western blot method was devised to detect CAF in sera of humans. A first trial on consenting blood donors (n=169; age 19-74 years) detected CAF in the limited range of 2.76 +/- 0.95 ng/ml. In sarcopenia patients (diagnosed according to clinical and instrumental standards) mean CAF levels were significantly elevated (p=9.8E10-9; n=73; age 65-87 years) compared to aged matched controls. Of all sarcopenia patients, 40% had elevated, non-overlapping CAF levels compared to controls. Evidence is presented for a pathogenic role of the agrin/neurotrypsin system in a substantial subset of sarcopenia patients. These patients are characterized by elevated CAF blood levels compared to aged-matched healthy volunteers suggesting the identification of an agrin-dependent form of sarcopenia. Elevated CAF levels in a large subpopulation of sarcopenic patients suggest the existence of a specific form of sarcopenia for which CAF could become a biomarker and a new target for therapeutic interventions. The feasibility of this approach was demonstrated by the development of a small molecule capable of inhibiting neurotrypsin in vitro and in vivo. (C) 2012 Elsevier Inc. All rights reserved.