Dystrophin restoration therapy improves both the reduced excitability and the force drop induced by lengthening contractions in dystrophic mdx skeletal muscle
Dystrophin restoration therapy improves both the reduced excitability and the force drop induced by lengthening contractions in dystrophic mdx skeletal muscle
复制标题
肌营养不良蛋白恢复疗法可改善营养不良性 mdx 骨骼肌因延长收缩而引起的兴奋性降低和力下降
作者：
P. Roy;F. Rau;J. Ochala;J. Messéant;B. Fraysse;J. Lainé;O. Agbulut;G. Butler;D. Furling;A. Ferry
背景对收缩诱导的骨骼肌损伤（脆性）的更大易感性是一个重要的营养不良特征，也是测试杜氏肌营养不良症的临床前肌营养不良蛋白治疗的工具。然而，这些疗法如何减少肌肉脆性尚不清楚。MethodsTo解决这个问题，我们首先确定的事件（S）的兴奋-收缩周期，这是/被改变后延长（偏心）收缩在mdx muscle.ResultsWe发现，立即力下降延长收缩，肌肉脆性的一个广泛使用的措施，与肌肉兴奋性降低。此外，力下降可以通过未受伤肌肉的肌肉兴奋的实验性减少来模拟。此外，力下降是不相关的主要神经肌肉传递失败，兴奋收缩解偶联，肌原纤维损伤。其次，重要的是，功能性截短的肌营养不良蛋白在肌肉中的mdx小鼠使用外显子跳跃策略的重新表达部分地防止了延长contractions.ConclusionWe后力下降和肌肉兴奋性的降低首次证明，（i）增加的易感性，以收缩诱导的肌肉损伤mdx小鼠主要是由于肌肉兴奋性降低;（ii）基于肌营养不良蛋白的治疗通过防止肌肉兴奋性的降低来改善营养不良骨骼肌的脆性。
BackgroundThe greater susceptibility to contraction-induced skeletal muscle injury (fragility) is an important dystrophic feature and tool for testing preclinic dystrophin-based therapies for Duchenne muscular dystrophy. However, how these therapies reduce the muscle fragility is not clear.MethodsTo address this question, we first determined the event(s) of the excitation-contraction cycle which is/are altered following lengthening (eccentric) contractions in the mdx muscle.ResultsWe found that the immediate force drop following lengthening contractions, a widely used measure of muscle fragility, was associated with reduced muscle excitability. Moreover, the force drop can be mimicked by an experimental reduction in muscle excitation of uninjured muscle. Furthermore, the force drop was not related to major neuromuscular transmission failure, excitation-contraction uncoupling, and myofibrillar impairment. Secondly, and importantly, the re-expression of functional truncated dystrophin in the muscle of mdx mice using an exon skipping strategy partially prevented the reductions in both force drop and muscle excitability following lengthening contractions.ConclusionWe demonstrated for the first time that (i) the increased susceptibility to contraction-induced muscle injury in mdx mice is mainly attributable to reduced muscle excitability; (ii) dystrophin-based therapy improves fragility of the dystrophic skeletal muscle by preventing reduction in muscle excitability.
影响因子：
3.5
作者：
L. Rodino-Klapac;P. Janssen;K. Shontz;Benjamin D. Canan;C. Montgomery;D. Griffin;K. Heller;K. Heller-K.
通讯作者：
L. Rodino-Klapac;P. Janssen;K. Shontz;Benjamin D. Canan;C. Montgomery;D. Griffin;K. Heller;K. Heller-K.
DOI：
10.1073/pnas.90.8.3710
发表时间：
1993-04-15
影响因子：
11.1
作者：
PETROF, BJ;SHRAGER, JB;SWEENEY, HL
通讯作者：
SWEENEY, HL