Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of Caenorhabditis elegans and its functional response to drugs.
Muscle strength deficiency and mitochondrial dysfunction in a muscular dystrophy model of Caenorhabditis elegans and its functional response to drugs.
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秀丽隐杆线虫肌营养不良模型中的肌力缺乏和线粒体功能障碍及其对药物的功能反应。
DOI：
10.1242/dmm.036137
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发表时间：
2018-12-04
影响因子：
4.3
通讯作者：
Vanapalli SA
中科院分区：
文献类型：
--
作者：
Hewitt JE;Pollard AK;Lesanpezeshki L;Deane CS;Gaffney CJ;Etheridge T;Szewczyk NJ;Vanapalli SA
肌肉力量是用于监测人肌营养不良症（包括杜氏肌营养不良症和贝克肌营养不良症）进展的关键临床参数。虽然秀丽隐杆线虫是一种用于研究肌营养不良症的机制和治疗的已建立的遗传模型，但在这种疾病模型中缺乏类似的基于力量的测量。在这里，我们描述了直接测量肌营养不良蛋白缺陷的C。elegans突变体使用微柱为基础的力测量系统称为NemaFlex。我们发现dys-1（eg 33）突变体，而不是dys-1（cx 18）突变体，在成年早期明显弱于它们的野生型对应物，不能以野生型速率在液体中颠簸，在体壁肌肉中显示线粒体网络碎片，并且具有异常高的基线线粒体呼吸。此外，用泼尼松（人类肌营养不良症的标准治疗）和褪黑激素治疗都能改善dys-1（eg 33）中的肌肉力量、抖动率和线粒体网络完整性，泼尼松治疗还能使基线呼吸恢复到正常水平。因此，我们的结果表明，dys-1（eg 33）菌株比dys-1（cx 18）更临床相关的肌营养不良症研究在C。优雅的这一发现与新的NemaFlex平台相结合，可作为一种有效的工作流程，用于识别可提高C. elegans肌营养不良模型。本研究也为进一步探讨肌营养不良蛋白缺陷型C.优雅的，从而产生了可转化为人类肌肉萎缩症的知识。编辑的选择：肌营养不良蛋白缺陷型秀丽隐杆线虫具有可测量的弱肌肉力量和线粒体功能障碍，并且它们响应于治疗人类杜氏肌营养不良症的药物治疗标准。
Muscle strength is a key clinical parameter used to monitor the progression of human muscular dystrophies, including Duchenne and Becker muscular dystrophies. Although Caenorhabditis elegans is an established genetic model for studying the mechanisms and treatments of muscular dystrophies, analogous strength-based measurements in this disease model are lacking. Here, we describe the first demonstration of the direct measurement of muscular strength in dystrophin-deficient C. elegans mutants using a micropillar-based force measurement system called NemaFlex. We show that dys-1(eg33) mutants, but not dys-1(cx18) mutants, are significantly weaker than their wild-type counterparts in early adulthood, cannot thrash in liquid at wild-type rates, display mitochondrial network fragmentation in the body wall muscles, and have an abnormally high baseline mitochondrial respiration. Furthermore, treatment with prednisone, the standard treatment for muscular dystrophy in humans, and melatonin both improve muscular strength, thrashing rate and mitochondrial network integrity in dys-1(eg33), and prednisone treatment also returns baseline respiration to normal levels. Thus, our results demonstrate that the dys-1(eg33) strain is more clinically relevant than dys-1(cx18) for muscular dystrophy studies in C. elegans. This finding, in combination with the novel NemaFlex platform, can be used as an efficient workflow for identifying candidate compounds that can improve strength in the C. elegans muscular dystrophy model. Our study also lays the foundation for further probing of the mechanism of muscle function loss in dystrophin-deficient C. elegans, leading to knowledge translatable to human muscular dystrophy. Editor's choice: Dystrophin-deficient Caenorhabditis elegans have measurably weak muscle strength and mitochondrial dysfunction, and they respond to drug treatments standard in treating human Duchenne muscular dystrophy.
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影响因子：
2.2
作者：
Bessou, C;Giugia, JB;Ségalat, L
通讯作者：
Ségalat, L
影响因子：
10.3
作者：
Hibaoui, Youssef;Reutenauer-Patte, Julie;Dorchies, Olivier M.
通讯作者：
Dorchies, Olivier M.
影响因子：
10.3
作者：
Chahbouni, Mariam;Escames, Germaine;Acuna-Castroviejo, Dario
通讯作者：
Acuna-Castroviejo, Dario
影响因子：
3.5
作者：
Brouilly, Nicolas;Lecroisey, Claire;Gieseler, Kathrin
通讯作者：
Gieseler, Kathrin
影响因子：
6
作者：
Jacobs, SCJM;Bootsma, AL;Wokke, JHJ
通讯作者：
Wokke, JHJ