Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice.-猫眼课题宝

全身给予 IGF-I 可增强 mdx 营养不良小鼠骨骼肌的氧化状态并减少收缩引起的损伤。

DOI：

10.1152/ajpendo.00101.2006

发表时间：

2006

期刊：

American journal of physiology. Endocrinology and metabolism

影响因子：

通讯作者：

中科院分区：

文献类型：

作者：

J. Schertzer;J. Ryall;G. Lynch

Dystrophin的缺失和由此导致的dystrophin糖蛋白复合体的破坏使营养不良患者和营养不良的mdx小鼠的骨骼肌容易受到收缩诱导的损伤。减少收缩引起的损伤的策略是至关重要的，因为这种损伤模式有助于营养不良病理中肌纤维破裂的病因。转基因过表达胰岛素样生长因子-I(IGF-I)可引起mdx小鼠肌纤维肥大，增加肌力产生，改善营养不良病理。相比之下，持续外源性低剂量(1.0-1.5 mg·kg(-1)·day(-1))的IGF-I给MDX小鼠的主要效果是肌肉表型从快速糖酵解转变为更氧化、更耐疲劳、更慢的肌肉，而肌纤维横截面积、肌肉质量或最大力量生产能力没有变化。我们发现，给MDX小鼠注射外源性IGF-I可以增加肌纤维琥珀酸脱氢酶的活性，使整个肌球蛋白重链亚型的组成向较慢的表型转变，最重要的是，减少了收缩导致的胫骨前肌损伤。经两次损伤性延长收缩后，经IGF-I治疗的mdx鼠胫前肌的力量缺陷(53+/-4%)较未治疗的mdx小鼠(70+/-5%)显著减少(P&lt；0.05)。这些结果进一步证明，给予IGF-I可以增强营养不良骨骼肌的功能特性，并且与转基因小鼠或病毒介导的过度表达的结果相比，突出了不同内分泌因子传递模式的差异。

The absence of dystrophin and resultant disruption of the dystrophin glycoprotein complex renders skeletal muscles of dystrophic patients and dystrophic mdx mice susceptible to contraction-induced injury. Strategies to reduce contraction-induced injury are of critical importance, because this mode of damage contributes to the etiology of myofiber breakdown in the dystrophic pathology. Transgenic overexpression of insulin-like growth factor-I (IGF-I) causes myofiber hypertrophy, increases force production, and can improve the dystrophic pathology in mdx mice. In contrast, the predominant effect of continuous exogenous administration of IGF-I to mdx mice at a low dose (1.0-1.5 mg.kg(-1).day(-1)) is a shift in muscle phenotype from fast glycolytic toward a more oxidative, fatigue-resistant, slow muscle without alterations in myofiber cross-sectional area, muscle mass, or maximum force-producing capacity. We found that exogenous administration of IGF-I to mdx mice increased myofiber succinate dehydrogenase activity, shifted the overall myosin heavy chain isoform composition toward a slower phenotype, and, most importantly, reduced contraction-induced damage in tibialis anterior muscles. The deficit in force-producing capacity after two damaging lengthening contractions was reduced significantly in tibialis anterior muscles of IGF-I-treated (53 +/- 4%) compared with untreated mdx mice (70 +/- 5%, P < 0.05). The results provide further evidence that IGF-I administration can enhance the functional properties of dystrophic skeletal muscle and, compared with results in transgenic mice or virus-mediated overexpression, highlight the disparities in different models of endocrine factor delivery.