Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1
Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1
复制标题
DOI：
10.1124/jpet.102.041343
复制
发表时间：
2003-01-01
影响因子：
3.5
通讯作者：
Camerino, DC
中科院分区：
文献类型：
--
作者：
De Luca, A;Pierno, S;Camerino, DC
临床前筛选比类固醇更安全且对杜氏肌营养不良症有益的禁用药物。能够减少钙诱导的变性（牛磺酸或肌酸，食物中10%）或刺激再生的化合物[胰岛素样生长因子-1（IGF-1）; 50或500 μ g/kg s.c.]给予在跑步机上进行慢性运动的MDX小鼠4 - 8周，这是使营养不良进展恶化的方案。α-甲基-泼尼松龙（PDN; lmg/kg）用作阳性对照。在体内评价了对前肢力量的影响，在体外评价了对宏观氯离子电导（gCl）（mdx肌肉中退化-再生事件的指数）和机械阈值（兴奋-收缩耦合的钙敏感指数）的电生理影响。该运动通过进一步降低已经很低的退化隔膜（DIA）值并完全阻碍再生趾长伸肌（EDL）mdx肌肉典型的gCl增加，产生了明显的虚弱和gCl损伤。mdx EDL收缩的已经为负的电压阈值也略微恶化。牛磺酸>肌酸> IGF-1抵消了运动引起的虚弱。gCl的改善是药物和肌肉特异性的：牛磺酸在EDL中有效，但在DIA肌肉中无效; IGF-1和PDN在两种肌肉中完全恢复，而肌酸无效。在体外未处理的肌肉中观察到IGF-1对gCl的急性作用，但在IGF-1处理的运动mdx肌肉中未观察到。牛磺酸> PDN > IGF-1，但肌酸，显着改善的负阈值电压值的EDL纤维。结果预测了牛磺酸和IGF-1对治疗人类营养不良症的潜在益处。
A preclinical screening for prompt-to-use drugs that are safer than steroids and beneficial in Duchenne muscular dystrophy was performed. Compounds able to reduce calcium-induced degeneration (taurine or creatine 10% in chow) or to stimulate regeneration [insulin-like growth factor-1 (IGF-1); 50 or 500 mug/kg s.c.] were administered for 4 to 8 weeks to mdx mice undergoing chronic exercise on a treadmill, a protocol to worsen dystrophy progression. alpha-Methyl-prednisolone (PDN; 1 mg/kg) was used as positive control. The effects were evaluated in vivo on forelimb strength and in vitro electrophysiologically on the macroscopic chloride conductance (gCl), an index of degeneration-regeneration events in mdx muscles, and on the mechanical threshold, a calcium-sensitive index of excitation-contraction coupling. The exercise produced a significant weakness and an impairment of gCl, by further decreasing the already low value of degenerating diaphragm (DIA) and fully hampering the increase of gCl typical of regenerating extensor digitorum longus (EDL) mdx muscle. The already negative voltage threshold for contraction of mdx EDL was also slightly worsened. Taurine > creatine > IGF-1 counteracted the exercise-induced weakness. The amelioration of gCl was drug- and muscle-specific: taurine was effective in EDL, but not in DIA muscle; IGF-1 and PDN were fully restorative in both muscles, whereas creatine was ineffective. An acute effect of IGF-1 on gCl was observed in vitro in untreated, but not in IGF-1-treated exercised mdx muscles. Taurine > PDN > IGF-1, but not creatine, significantly ameliorated the negative threshold voltage values of the EDL fibers. The results predict a potential benefit of taurine and IGF-1 for treating human dystrophy.