Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy
Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy
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DOI：
10.1096/fj.10-176727
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发表时间：
2011-06-01
期刊：
影响因子：
4.8
通讯作者：
Larsson, Lars
中科院分区：
文献类型：
--
作者：
Ochala, Julien;Lehtokari, Vilma-Lotta;Larsson, Lars
Nebulin是在骨骼肌中高水平表达的巨大蛋白质。星云蛋白基因（NEB）的突变导致肌肉无力和各种先天性肌病。尽管越来越多的临床和科学的兴趣，虚弱的发病机制仍然未知。因此，本研究旨在揭示潜在的分子机制。因此，我们记录和分析的力学以及X-射线衍射图案的人膜透化的单肌纤维表达星云蛋白突变。结果表明，在收缩过程中，附着到肌动蛋白的肌球蛋白头的循环速率显着扰动，导致肌球蛋白-肌动蛋白相互作用的分数在强结合状态的减少。这种现象阻止了完全的细丝激活，更特别地阻止了正确和完全的原肌球蛋白运动，进一步限制了肌球蛋白跨桥的额外结合。在细胞水平上，这会降低力量产生能力，总体而言，会引起肌肉无力。为了扭转这种负面的事件级联反应，未来潜在的治疗干预措施应该关注触发成分，即改变的肌球蛋白跨桥循环动力学。Ochala，J.，Lehtokari，V. L.，Iwamoto，H.，Li，M.，冯汉卿Z.，Jin，J.P.，Yagi，N.，Walland-Pettersson，C.佩尼松-贝涅尔岛拉尔森湖肌球蛋白跨桥循环动力学中断触发了星云蛋白相关肌病的肌无力。FASEB J.25，1903-1913（2011）。www.fasebj.org
Nebulin is a giant protein expressed at high levels in skeletal muscle. Mutations in the nebulin gene (NEB) lead to muscle weakness and various congenital myopathies. Despite increasing clinical and scientific interest, the pathogenesis of weakness remains unknown. The present study, therefore, aims at unraveling the underlying molecular mechanisms. Hence, we recorded and analyzed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibers expressing nebulin mutations. Results demonstrated that, during contraction, the cycling rate of myosin heads attaching to actin is dramatically perturbed, causing a reduction in the fraction of myosin-actin interactions in the strong binding state. This phenomenon prevents complete thin-filament activation, more especially proper and full tropomyosin movement, further limiting additional binding of myosin cross-bridges. At the cell level, this reduces the force-generating capacity and, overall, provokes muscle weakness. To reverse such a negative cascade of events, future potential therapeutic interventions should, therefore, focus on the triggering component, the altered myosin cross-bridge cycling kinetics.-Ochala, J., Lehtokari, V.-L., Iwamoto, H., Li, M., Feng, H.-Z., Jin, J. P., Yagi, N., Wallgren-Pettersson, C. Penisson-Besnier, I., Larsson, L. Disrupted myosin cross-bridge cycling kinetics triggers muscle weakness in nebulin-related myopathy. FASEB J. 25, 1903-1913 (2011). www.fasebj.org