Children's National Medical Center, Washington DC, United States of America.
PLoS One. 2012;7(4):e34204. doi: 10.1371/journal.pone.0034204. Epub 2012 Apr 3.
Dmd(mdx) (mdx) mice are used as a genetic and biochemical model of dystrophin deficiency. The long-term consequences of glucocorticoid (GC) treatment on dystrophin-deficient skeletal and heart muscle are not yet known. Here we used systematic phenotyping to assess the long-term consequences of GC treatment in mdx mice. Our investigation addressed not only the effects of GC on the disease phenotype but also the question of whether GCs can be used as a positive control for preclinical drug evaluations.
We performed nine pre-clinical efficacy trials (treated N = 129, untreated N = 106) of different durations in 9-to-50-week-old dystrophic mdx mice over a 3-year time period using standardized methods. In all these trials, we used either 1 mg/kg body weight of prednisone or 5 mg/kg body weight of prednisolone as positive controls to compare the efficacy of various test drugs. Data from untreated controls and GC-treated mice in the various trials have been pooled and analyzed to assess the effects of GCs on dystrophin-deficient skeletal and cardiac muscles of mdx mice. Our results indicate that continuous GC treatment results in early (e.g., at 50 days) improvements in normalized parameters such as grip strength, motor coordination and maximal in vitro force contractions on isolated EDL muscle, but these initial benefits are followed by a progressive loss of muscle strength after 100 days. We also found a significant increase in heart fibrosis that is reflected in a significant deterioration in cardiac systolic function after 100 days of treatment.
Continuous administration of prednisone to mdx mice initially improves skeletal muscle strength, but further therapy result in deterioration of muscle strength and cardiac function associated with enhanced cardiac fibrosis. These results suggest that GCs may not serve as an appropriate positive control for long-term mdx mouse preclinical trials.
Dmd(mdx)（mdx）小鼠被用作肌营养不良症缺乏症的遗传和生化模型。糖皮质激素（GC）治疗对肌营养不良症缺乏的骨骼肌和心肌的长期后果尚不清楚。在这里，我们使用系统表型分析来评估 GC 治疗在 mdx 小鼠中的长期后果。我们的研究不仅关注 GC 对疾病表型的影响，还关注 GC 是否可以用作临床前药物评估的阳性对照。
我们在 3 年时间内对 9 至 50 周龄的肌营养不良症 mdx 小鼠进行了 9 项不同持续时间的临床前疗效试验（治疗 N = 129，未治疗 N = 106），使用了标准化方法。在所有这些试验中，我们使用 1mg/kg 体重的泼尼松或 5mg/kg 体重的泼尼松龙作为阳性对照，以比较各种测试药物的疗效。未治疗对照和各种试验中 GC 治疗小鼠的数据已被汇总和分析，以评估 GC 对 mdx 小鼠骨骼肌和心肌的影响。我们的结果表明，连续 GC 治疗可导致正常化参数（如握力、运动协调和分离的 EDL 肌肉的最大体外力收缩）的早期（例如，50 天）改善，但这些初始益处随后在 100 天后出现肌肉力量的逐渐丧失。我们还发现心脏纤维化显著增加，这反映在治疗 100 天后心脏收缩功能显著恶化。
连续给予泼尼松龙治疗 mdx 小鼠可最初改善骨骼肌力量，但进一步的治疗会导致肌肉力量恶化和心脏功能恶化，伴有增强的心脏纤维化。这些结果表明，GC 可能不适用于 mdx 小鼠的长期临床前试验的阳性对照。
