Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases.
Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases.
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作者：
在神经肌肉疾病中，有限的神经肌肉输入会导致肌肉无力，原因是肌肉神经支配密度、神经肌肉接头激活率或突触传递效率降低。我们开发了一种小分子快速骨骼肌钙蛋白激活剂CK-2017357，作为一种手段，当继发性神经肌肉疾病导致神经肌肉输入减少时，通过放大肌肉的反应来增加肌肉力量。CK-2017357选择性地与快速的骨骼肌钙蛋白复合体结合，减缓肌钙蛋白C的钙释放速度，并使肌肉对钙敏感。因此，肌肉纤维的力-钙关系向左移动，神经-肌肉对的力-频率关系也是如此。在体外和体内，CK-2017357以次最大刺激率增加力量的产生。重要的是，在一种神经肌肉疾病重症肌无力模型中，我们发现快速骨骼肌钙蛋白复合体对钙的敏化可以改善单剂CK-2017357后的肌力和握力。肌钙蛋白激活可能为改善神经肌肉功能受损疾病的体力活动提供一种新的治疗方法。
Limited neuromuscular input results in muscle weakness in neuromuscular disease either because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small molecule fast skeletal troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Binding selectively to the fast skeletal troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair. In vitro and in vivo, CK-2017357 increases the production of force at sub-maximal stimulation rates. Importantly, we show that sensitization of the fast skeletal troponin complex to calcium improves muscle force and grip strength immediately after single doses of CK-2017357 in a model of neuromuscular disease, myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.
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影响因子：
3
作者：
Poole, Katrina J. V.;Lorenz, Michael;Holmes, Kenneth C.
通讯作者：
Holmes, Kenneth C.
影响因子：
4.3
作者：
Ling SM;Conwit RA;Ferrucci L;Metter EJ
通讯作者：
Metter EJ
DOI：
10.1126/science.1200113
发表时间：
2011-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Malik FI;Hartman JJ;Elias KA;Morgan BP;Rodriguez H;Brejc K;Anderson RL;Sueoka SH;Lee KH;Finer JT;Sakowicz R;Baliga R;Cox DR;Garard M;Godinez G;Kawas R;Kraynack E;Lenzi D;Lu PP;Muci A;Niu C;Qian X;Pierce DW;Pokrovskii M;Suehiro I;Sylvester S;Tochimoto T;Valdez C;Wang W;Katori T;Kass DA;Shen YT;Vatner SF;Morgans DJ
通讯作者：
Morgans DJ
影响因子：
--
作者：
BROOKS, SV;FAULKNER, JA
通讯作者：
FAULKNER, JA
影响因子：
5.6
作者：
Bloemink, M. J.;Adamek, N.;Geeves, M. A.
通讯作者：
Geeves, M. A.