GsMTx4-D provides protection to the D2.mdx mouse.
GsMTx4-D provides protection to the D2.mdx mouse.
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DOI：
10.1016/j.nmd.2018.07.005
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Suchyna TM
中科院分区：
文献类型：
--
作者：
Ward CW;Sachs F;Bush ED;Suchyna TM
杜氏肌营养不良症是一种限制生命的肌肉疾病，目前没有有效的治疗方法。尽管有越来越多的证据表明机械敏感性离子通道的失调是营养不良发病机制的重要贡献者，但缺乏针对这些通道的有效药理学策略。GsMTx 4及其对映体GsMTx 4-D是具有相同活性的机械敏感性通道的肽抑制剂。在以前的研究中，急性体外应用GsMTx 4营养不良的小鼠肌肉有效地减少了过量的MSC依赖性钙内流与收缩诱导的肌肉损伤。在此，我们试图确定用GsMTx 4-D的体内治疗是否在D2.mdx小鼠中提供益处。GsMTx 4-D通过皮下注射给药4周后，半衰期为1周。根据这些结果，D2.mdx小鼠随后通过皮下注射GsMTx 4-D方案治疗6周，随后测定肌肉质量、肌肉对离心收缩损伤的易感性和疾病进展的多种组织学指标。小鼠表现出肌肉质量损失减少和对收缩诱导的损伤的敏感性降低。这些保护作用在没有减少纤维化的情况下实现，支持GsMTx 4-D直接作用于肌肉细胞的模型。我们提出GsMTx 4-D代表了一种有前途的减缓疾病进展的新疗法，并可能补充其他疗法，如抗炎药和基因替代策略。
Duchenne muscular dystrophy is a life-limiting muscle disease that has no current effective therapy. Despite mounting evidence that dysregulation of mechanosensitive ion channels is a significant contributor to dystrophy pathogenesis, effective pharmacologic strategies targeting these channels are lacking. GsMTx4, and its enantiomer GsMTx4-D, are peptide inhibitors of mechanosensitive channels with identical activity. In previous studies, acute in vitro application of GsMTx4 to dystrophic murine muscle effectively reduced the excess MSC dependent calcium influx linked to contraction-induced muscle damage. Here we sought to determine if in vivo treatment with GsMTx4-D proffered benefit in the D2.mdx mouse. GsMTx4-D showed a 1-week half-life when administered by subcutaneous injection over four weeks. Informed by these results, D2.mdx mice were then treated by a subcutaneous injection regimen of GsMTx4-D for six weeks followed by determination of muscle mass, muscle susceptibility to eccentric contraction injury and multiple histological indicators of disease progression. The mice showed a reduction in the loss of muscle mass and a decrease in susceptibility to contraction induced injury. These protective effects were realized without reduction in fibrosis, supporting a model where GsMTx4-D acts directly on muscle cells. We propose GsMTx4-D represents a promising new therapy to slow disease progression and may complement other therapies such as anti-inflammatory agents and gene-replacement strategies.
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影响因子：
5.5
作者：
Gailly, P.;De Backer, F.;Gillis, J. M.
通讯作者：
Gillis, J. M.
影响因子：
3.8
作者：
Haws, CM;Winegar, BD;Lansman, JB
通讯作者：
Lansman, JB
影响因子：
6
作者：
Jorgensen, Louise H.;Blain, Alison;Lochmueller, Hanns
通讯作者：
Lochmueller, Hanns
DOI：
10.1523/jneurosci.0893-09.2009
发表时间：
2009-05-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Alessandri-Haber N;Dina OA;Chen X;Levine JD
通讯作者：
Levine JD
影响因子：
5.5
作者：
De Backer, F;Vandebrouck, C;Gillis, JM
通讯作者：
Gillis, JM