Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations.
Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations.
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DOI：
10.1136/jmedgenet-2012-101470
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发表时间：
2013-06
影响因子：
4
通讯作者：
Granzier H
中科院分区：
文献类型：
--
作者：
de Winter JM;Buck D;Hidalgo C;Jasper JR;Malik FI;Clarke NF;Stienen GJ;Lawlor MW;Beggs AH;Ottenheijm CA;Granzier H
线状体肌病是最常见的非营养不良性先天性肌病，是由细丝基因突变引起的，其中星云蛋白基因是最常见的一种。nebulin基因编码巨大的肌节蛋白nebulin，其在骨骼肌收缩性能中起着至关重要的作用。肌无力是具有星云蛋白突变的线状体肌病患者的标志性特征，并且是由收缩蛋白功能的变化引起的，包括力产生的较低的钙敏感性。到目前为止，还没有治疗线状体肌病肌无力的方法。在这里，我们研究了新的快速骨骼肌肌钙蛋白激活剂CK-2066260的能力，以增加在次最大钙水平的肌细胞从nebulin突变的线虫性肌病患者的力量产生。在从冷冻患者活检分离的透化肌细胞中测定收缩蛋白功能。评估了5 µM CK-2066260对力产生的影响。与对照组相比，这些患者的肌细胞中的神经球蛋白浓度严重降低，而肌原纤维超微结构基本保留。与对照组相比，患者的最大主动张力和力产生的钙敏感性均较低。重要的是，CK-2066260大大增加了患者产生力的钙敏感性，而不影响激活的协同性，其水平超过了未治疗对照肌肉中观察到的水平。快速骨骼肌钙蛋白激活是一种治疗机制，以增强收缩蛋白功能的线状体肌病患者与nebulin突变和其他神经肌肉疾病。
Nemaline myopathy—the most common non-dystrophic congenital myopathy—is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebulin, which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK-2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations. Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 µM CK-2066260 on force production was assessed. Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calcium-sensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation—without affecting the cooperativity of activation—in patients to levels that exceed those observed in untreated control muscle. Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.
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影响因子：
4.8
作者：
Chandra, Murali;Mamidi, Ranganath;Granzier, Henk
通讯作者：
Granzier, Henk
影响因子：
3.5
作者：
Ottenheijm, Coen A. C.;Witt, Christian C.;Granzier, Henk
通讯作者：
Granzier, Henk
影响因子：
9.9
作者：
Ryan, MM;Ilkovski, B;Beggs, AH
通讯作者：
Beggs, AH
DOI：
10.1164/rccm.200805-732oc
发表时间：
2009-01-01
影响因子：
24.7
作者：
van Hees, Hieronymus W. H.;Dekhuijzen, P. N. Richard;Heunks, Leo M. A.
通讯作者：
Heunks, Leo M. A.
影响因子：
4.8
作者：
Ochala, Julien;Lehtokari, Vilma-Lotta;Larsson, Lars
通讯作者：
Larsson, Lars