Targeted expression of insulin-like growth factor-1 reduces early myofiber necrosis in dystrophic mdx mice
Targeted expression of insulin-like growth factor-1 reduces early myofiber necrosis in dystrophic mdx mice
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DOI：
10.1016/j.ymthe.2004.07.026
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发表时间：
2004-11-01
影响因子：
12.4
通讯作者：
Grounds, MD
中科院分区：
文献类型：
--
作者：
Shavlakadze, T;White, J;Grounds, MD
Duchenne 肌营养不良症和 mdx 小鼠的营养不良性肌纤维坏死是由于肌膜下肌营养不良蛋白缺陷导致肌膜膜脆性和撕裂，从而导致肌纤维破坏。本研究专门测试 mdx/mIGF-1 转基因小鼠中 mIGF-1 的过度表达是否会减少营养不良急性发作期（第 21 天）的肌纤维分解。对 15 至 30 日龄的 mdx/mIGF-1 及其 mdx 同窝小鼠的肌肉损伤程度和肌纤维伊文思蓝染料 (EBD) 染色进行组织学定量。出生后 21-22 天，mIGF-1 的过度表达可显着降低胫骨前肌和股四头肌的肌纤维损伤程度（组织学和 EBD 染色）高达 97%。在 mdx 膈肌中，肌肉分解的发生较早（出生后 15 天），但在 mdx/IGF-1 小鼠的第一个月内，IGF-1 没有明显的保护作用。这些新的观察结果表明，mdx 肌纤维内 mIGF-1 的增加特异性地减少了肌肉退化急性发作期间营养不良性肌肉的分解。这种作用机制可以解释过度表达 mIGF-1 的 mdx 小鼠中营养不良的严重程度长期降低的原因，并为治疗策略提供了有希望的机会。
Necrosis of dystrophic myofibers in Duchenne muscular dystrophy and mdx mice results from defects in the subsarcolemmal protein dystrophin that cause membrane fragility and tears in the sarcolemma, and these lead to the destruction of the myofibers. The present study specifically tests whether overexpression of mIGF-1 in mdx/mIGF-1 transgenic mice reduces myofiber breakdown during the acute onset phase of dystrophy (at 21 days). The extent of muscle damage and Evans blue dye (EBD) staining of myofibers was quantitated histologically for mdx/mIGF-1 and their mdx littermates from 15 to 30 days of age. Overexpression, of mIGF-1 strikingly reduced the extent of myofiber damage (histology and EBD staining) by up to 97% in tibialis anterior and quadriceps muscles at 21-22 days after birth. In the mdx diaphragm, the onset of muscle breakdown was earlier (by 15 days after birth) but no significant protective effect of IGF-1 was apparent within the first month of age in mdx/IGF-1 mice. These novel observations show that increased mIGF-1 within mdx myofibers specifically reduces the breakdown of dystrophic muscle during the acute onset of muscle degeneration. This mechanism of action can account for the long-term reduced severity of the dystropathology in mdx mice that overexpress mIGF-1 and provides promising opportunities for therapeutic strategies.