Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo.
Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo.
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DOI：
10.1038/mtm.2015.42
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Metzger JM
中科院分区：
文献类型：
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作者：
Houang EM;Haman KJ;Filareto A;Perlingeiro RC;Bates FS;Lowe DA;Metzger JM
杜氏肌营养不良症 (DMD) 是一种导致横纹肌退化的致命疾病。 DMD 的一种独特治疗方法是使用合成膜稳定剂来保护脆弱的营养不良性肌膜免受收缩引起的机械应力。基于嵌段共聚物的膜稳定剂泊洛沙姆 188 (P188) 已被证明可以保护营养不良的心肌。相比之下，合成膜稳定剂保护脆弱的 DMD 骨骼肌的能力尚不清楚。由于心肌和骨骼肌具有不同的结构和功能特征，包括激活机制的差异、肌膜磷脂组成的差异以及产生的力的大小和类型的差异，我们推测优化的膜稳定性可能本质上是不同的。我们的目标是利用药效学原理来评估 DMD 骨骼肌的膜稳定疗法。结果表明，通过优化药效学指导的泊洛沙姆递送途径，膜稳定效果显着不同。数据显示，皮下 P188 递送（而非血管内或腹膜内途径）为体内承受机械应力的营养不良肢体骨骼肌提供了显着的保护。此外，合成膜稳定剂的结构功能检查进一步强调了共聚物组成、分子量和剂量在泊洛沙姆体内药效优化中的重要性。
Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration. A unique therapeutic approach for DMD is the use of synthetic membrane stabilizers to protect the fragile dystrophic sarcolemma against contraction-induced mechanical stress. Block copolymer-based membrane stabilizer poloxamer 188 (P188) has been shown to protect the dystrophic myocardium. In comparison, the ability of synthetic membrane stabilizers to protect fragile DMD skeletal muscles has been less clear. Because cardiac and skeletal muscles have distinct structural and functional features, including differences in the mechanism of activation, variance in sarcolemma phospholipid composition, and differences in the magnitude and types of forces generated, we speculated that optimized membrane stabilization could be inherently different. Our objective here is to use principles of pharmacodynamics to evaluate membrane stabilization therapy for DMD skeletal muscles. Results show a dramatic differential effect of membrane stabilization by optimization of pharmacodynamic-guided route of poloxamer delivery. Data show that subcutaneous P188 delivery, but not intravascular or intraperitoneal routes, conferred significant protection to dystrophic limb skeletal muscles undergoing mechanical stress in vivo. In addition, structure-function examination of synthetic membrane stabilizers further underscores the importance of copolymer composition, molecular weight, and dosage in optimization of poloxamer pharmacodynamics in vivo.