Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage
Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage
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DOI：
10.1113/expphysiol.2008.042838
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发表时间：
2008-11-01
影响因子：
2.7
通讯作者：
Lynch, Gordon S.
中科院分区：
文献类型：
--
作者：
Gehrig, Stefan M.;Ryall, James G.;Lynch, Gordon S.
收缩介导的损伤是肌萎缩症病理生理的一个主要因素，因此可以减轻这种损伤的治疗具有临床意义。全身注射胰岛素样生长因子- i （IGF-I）已被证明可以改善营养不良mdx小鼠的肌肉功能，这种效果与向更氧化的肌肉表型转变和减少对收缩介导损伤的易感性有关。体内IGF- i的作用由IGF结合蛋白（igfbp）调节，IGF结合蛋白通常抑制IGF- i信号传导。我们测试了IGF-I类似物（LR IGF-I）的假设，它显著降低了对igfbp的结合亲和力，通过降低对肌肉损伤的易感性来改善营养不良病理。营养不良的mdx和野生型（C57BL/10）小鼠通过渗透微型泵连续给予LR IGF-I(类似于1.5 mg kg(-1) day(-1)) 4周。应用LR igf - 1可降低指长伸肌、比目鱼肌和膈肌对收缩损伤的易感性，这从延长收缩方案后较低的力量缺陷中可见一斑。与igf - 1提供的保护机制相反，LR igf - 1提供的保护与肌肉疲劳和氧化代谢的变化无关。本研究进一步表明，调节igf - 1信号传导对肌肉疾病具有治疗潜力。
Contraction-mediated injury is a major contributing factor to the pathophysiology of muscular dystrophy and therefore therapies that can attenuate this type of injury have clinical relevance. Systemic administration of insulin-like growth factor-I (IGF-I) has been shown to improve muscle function in dystrophic mdx mice, an effect associated with a shift towards a more oxidative muscle phenotype and a reduced susceptibility to contraction-mediated damage. The actions of IGF-I in vivo are modulated by IGF binding proteins (IGFBPs), which generally act to inhibit IGF-I signalling. We tested the hypothesis that an analogue of IGF-I (LR IGF-I), which has significantly reduced binding affinity for IGFBPs, would improve the dystrophic pathology by reducing the susceptibility to muscle injury. Dystrophic mdx and wild-type (C57BL/10) mice were administered LR IGF-I continuously (similar to 1.5 mg kg(-1) day(-1)) via osmotic mini-pump for 4 weeks. Administration of LR IGF-I reduced the susceptibility of extensor digitorum longus, soleus and diaphragm muscles to contraction damage, as evident from lower force deficits after a protocol of lengthening contractions. In contrast to the mechanism of protection conferred by administration of IGF-I, the protection conferred by LR IGF-I was independent of changes in muscle fatigue and oxidative metabolism. This study further indicates that modulation of IGF-I signalling has therapeutic potential for muscular diseases.