Lack of CFTR in skeletal muscle predisposes to muscle wasting and diaphragm muscle pump failure in cystic fibrosis mice.
Lack of CFTR in skeletal muscle predisposes to muscle wasting and diaphragm muscle pump failure in cystic fibrosis mice.
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DOI：
10.1371/journal.pgen.1000586
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发表时间：
2009-07
期刊：
影响因子：
4.5
通讯作者：
Petrof BJ
中科院分区：
文献类型：
--
作者：
Divangahi M;Balghi H;Danialou G;Comtois AS;Demoule A;Ernest S;Haston C;Robert R;Hanrahan JW;Radzioch D;Petrof BJ
囊性纤维化（CF）患者通常具有骨骼肌的质量和强度降低，包括膈肌，呼吸的主要肌肉。在这里，我们表明，CF跨膜传导调节因子（CFTR）的缺乏在骨骼肌萎缩和功能障碍中起着内在的作用。在正常小鼠和人骨骼肌中，CFTR表达并与肌浆网相关蛋白共定位。CFTR缺陷型肌管在KCl诱导的去极化后表现出细胞内钙水平的增加，并且暴露于炎症环境诱导过度的NF-κ B易位和细胞因子/趋化因子基因上调。为了确定体内炎症环境的影响，产生了铜绿假单胞菌的持续肺部感染，在这些条件下，Cftr −/−小鼠的趋化力产生能力选择性降低。这与过度的促炎细胞因子表达以及参与肌肉萎缩的E3泛素连接酶（MuRF 1和atrogin-1）的上调有关。我们的结论是，内在的功能改变与骨骼肌CFTR的缺失有关，导致钙稳态失调，炎症/萎缩基因表达特征增强，肺部感染时呼吸无力增加。这些发现揭示了以前未被认识到的CFTR在骨骼肌功能中的作用，这可能对CF患者的恶病质和呼吸肌泵衰竭的发病机制具有重要意义。囊性纤维化是一种常染色体隐性遗传疾病，由CF跨膜传导调节因子（CFTR）突变引起，CFTR作为氯离子通道，也参与其他离子和蛋白质的调节。在大多数CF患者中，临床病程以肺部疾病和复发性肺部细菌感染为主。许多CF患者也有明显的骨骼肌萎缩和无力，这可能会影响最重要的呼吸肌，膈肌。虽然CF中的肌肉萎缩通常归因于体力活动减少和营养不良等因素，但我们的研究揭示了由于缺乏CFTR而导致的骨骼肌功能的内在缺陷。因此，我们发现CFTR通常存在于人类和小鼠的骨骼肌纤维中。在缺乏CFTR的CF肌细胞中，发现钙和炎症基因表达的异常升高。此外，在肺部感染期间，缺乏CFTR的膈肌表现出更大的虚弱和导致肌肉萎缩的基因的诱导。这些发现扩展了我们对导致CF运动受限和残疾的因素的理解，也对CF患者肺部感染期间呼吸肌衰竭的发病机制有影响。
Cystic fibrosis (CF) patients often have reduced mass and strength of skeletal muscles, including the diaphragm, the primary muscle of respiration. Here we show that lack of the CF transmembrane conductance regulator (CFTR) plays an intrinsic role in skeletal muscle atrophy and dysfunction. In normal murine and human skeletal muscle, CFTR is expressed and co-localized with sarcoplasmic reticulum-associated proteins. CFTR–deficient myotubes exhibit augmented levels of intracellular calcium after KCl-induced depolarization, and exposure to an inflammatory milieu induces excessive NF-kB translocation and cytokine/chemokine gene upregulation. To determine the effects of an inflammatory environment in vivo, sustained pulmonary infection with Pseudomonas aeruginosa was produced, and under these conditions diaphragmatic force-generating capacity is selectively reduced in Cftr −/− mice. This is associated with exaggerated pro-inflammatory cytokine expression as well as upregulation of the E3 ubiquitin ligases (MuRF1 and atrogin-1) involved in muscle atrophy. We conclude that an intrinsic alteration of function is linked to the absence of CFTR from skeletal muscle, leading to dysregulated calcium homeostasis, augmented inflammatory/atrophic gene expression signatures, and increased diaphragmatic weakness during pulmonary infection. These findings reveal a previously unrecognized role for CFTR in skeletal muscle function that may have major implications for the pathogenesis of cachexia and respiratory muscle pump failure in CF patients. Cystic fibrosis is an autosomal recessive disorder caused by mutations of the CF transmembrane conductance regulator (CFTR), which acts as a chloride channel and also participates in the regulation of other ions and proteins. In most CF patients, the clinical course is dominated by lung disease and recurrent pulmonary bacterial infections. Many CF patients also have significant skeletal muscle wasting and weakness, and this can affect the most essential breathing muscle, the diaphragm. Although muscle wasting in CF has generally been attributed to factors such as reduced physical activity and poor nutrition, our study reveals an intrinsic defect of skeletal muscle function caused by the lack of CFTR. Hence, we show that CFTR is normally found in skeletal muscle fibers of humans and mice. In CF muscle cells lacking CFTR, abnormal elevations of calcium and inflammatory gene expression are found. In addition, during pulmonary infections, diaphragm muscles lacking CFTR show greater weakness and induction of genes which cause muscle atrophy. These findings extend our understanding of the factors leading to exercise limitation and disability in CF and also have implications for the pathogenesis of respiratory muscle failure in CF patients during lung infections.
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影响因子：
37.8
作者：
Chen, H;Liu, LL;Duan, DY
通讯作者：
Duan, DY
DOI：
10.1164/ajrccm.157.4.9702081
发表时间：
1998-04-01
影响因子：
24.7
作者：
Gosselin, D;Stevenson, MM;Radzioch, D
通讯作者：
Radzioch, D
DOI：
10.1152/ajpcell.1998.275.1.c323
发表时间：
1998-07-01
影响因子：
5.5
作者：
Linsdell, P;Hanrahan, JW
通讯作者：
Hanrahan, JW
影响因子：
3.7
作者：
Lochmüller, H;Johns, T;Shoubridge, EA
通讯作者：
Shoubridge, EA
影响因子：
5.5
作者：
Coonan, JR;Lamb, GD
通讯作者：
Lamb, GD