Leupeptin-based inhibitors do not improve the mdx phenotype.
Leupeptin-based inhibitors do not improve the mdx phenotype.
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基于亮肽素的抑制剂不会改善 mdx 表型。
DOI：
10.1152/ajpregu.00586.2009
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Sweeney,HLee
中科院分区：
文献类型：
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作者：
Selsby,Joshua;Pendrak,Klara;Zadel,Monica;Tian,Zuozhen;Pham,Jennifer;Carver,Ted;Acosta,Pedro;Barton,Elisabeth;Sweeney,HLee
钙蛋白酶激活与杜氏肌营养不良症的疾病病理学有关。抑制钙蛋白酶被认为是一个很有前途的治疗靶点，它可以减少蛋白质降解，防止进行性纤维化。与此同时，关于钙蛋白酶抑制剂（一种内源性钙蛋白酶抑制剂）的升高是否会改变病理学，有相互矛盾的报道。我们比较了使用亮抑酶肽和将亮抑酶肽的抑制部分与肉毒碱连接（以增加肌肉摄取）的专利化合物（C101）对mdx小鼠的药理学钙蛋白酶抑制作用。给予C101 4周并没有改善mdx小鼠的肌肉组织学、功能或血清肌酸激酶水平。每天注射亮抑酶肽（36 mg/kg）6个月的Mdx小鼠也未能显示肌肉功能、组织学或肌酸激酶水平的改善。生化分析显示亮抑酶肽给药引起m-钙蛋白酶自溶和蛋白酶体活性增加，但钙蛋白酶抑制蛋白水平在治疗和未治疗的mdx小鼠之间相似。这些数据表明，由于骨骼肌通过增加多种降解途径对抗钙蛋白酶抑制剂的能力，钙蛋白酶的药理学抑制不是治疗杜氏肌营养不良症的有希望的干预措施。
Calpain activation has been implicated in the disease pathology of Duchenne muscular dystrophy. Inhibition of calpain has been proposed as a promising therapeutic target, which could lessen the protein degradation and prevent progressive fibrosis. At the same time, there are conflicting reports as to whether elevation of calpastatin, an endogenous calpain inhibitor, alters pathology. We compared the effects of pharmacological calpain inhibition in the mdx mouse using leupeptin and a proprietary compound (C101) that linked the inhibitory portion of leupeptin to carnitine (to increase uptake into muscle). Administration of C101 for 4 wk did not improve muscle histology, function, or serum creatine kinase levels in mdx mice. Mdx mice injected daily with leupeptin (36 mg/kg) for 6 mo also failed to show improved muscle function, histology, or creatine kinase levels. Biochemical analysis revealed that leupeptin administration caused an increase in m-calpain autolysis and proteasome activity, yet calpastatin levels were similar between treated and untreated mdx mice. These data demonstrate that pharmacological inhibition of calpain is not a promising intervention for the treatment of Duchenne muscular dystrophy due to the ability of skeletal muscle to counter calpain inhibitors by increasing multiple degradative pathways.