Skeletal Muscle Fibrosis in the mdx/utrn plus /- Mouse Validates Its Suitability as a Murine Model of Duchenne Muscular Dystrophy
Skeletal Muscle Fibrosis in the mdx/utrn plus /- Mouse Validates Its Suitability as a Murine Model of Duchenne Muscular Dystrophy
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DOI：
10.1371/journal.pone.0117306
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发表时间：
2015-01-21
期刊：
影响因子：
3.7
通讯作者：
Hoffman, Lisa M.
中科院分区：
文献类型：
--
作者：
Gutpell, Kelly M.;Hrinivich, William T.;Hoffman, Lisa M.
杜氏肌营养不良症(DMD)的各种治疗方法已经被研究过，但这些方法都没有对患者产生显著的长期效果。这种观察到的无效的原因之一可能是使用了不适当的动物模型来测试治疗剂。MDX小鼠是最广泛使用的DMD小鼠模型，但它不能模拟在患者中观察到的纤维化进展。其他DMD的小鼠模型也存在缺乏一个或两个utroin等位基因的情况，utroin是一种Dstrophin的功能类似物。本研究的目的是比较MDX、MDX/UTUN+/-和双基因敲除(DKO)小鼠模型中的纤维化和肌纤维损伤。我们使用Masson‘s三色染色和中央有核肌纤维百分比分别作为纤维化和肌纤维再生的指标，以评估来自年轻和老年野生型、MDX、MDX/UTUN+/-和dKO小鼠的横隔肌和腓肠肌的疾病进展。结果表明，8周龄的MDX/UTUN+/-和DKO后肢的腓肠肌出现纤维化，而年龄匹配的MDX腓肠肌没有纤维化(P=0.002)。MDX/UTUN+/-横隔肌中的胶原含量显著高于野生型动物相应横隔肌中的胶原含量，而MDX动物的相应横隔肌中的胶原含量无显著差异(p=0.0003)。与野生型对照组相比，老年mdx/UTUN+/-小鼠出现了横隔肌和腓肠肌的纤维化(p=0.003)。在老年小鼠中，MDX隔膜也有纤维化(p=0.0235)，而这些动物的腓肠肌没有纤维化。我们没有测量到野生型和MDX腓肠肌之间的胶原染色有显著差异。这项研究的结果支持了先前的报道，即中度感染的MDX/UTUN+/-小鼠是DMD的更好模型，我们在这里显示，这种差异在2个月大时就明显存在。
Various therapeutic approaches have been studied for the treatment of Duchenne muscular dystrophy (DMD), but none of these approaches have led to significant long-term effects in patients. One reason for this observed inefficacy may be the use of inappropriate animal models for the testing of therapeutic agents. The mdx mouse is the most widely used murine model of DMD, yet it does not model the fibrotic progression observed in patients. Other murine models of DMD are available that lack one or both alleles of utrophin, a functional analog of dystrophin. The aim of this study was to compare fibrosis and myofiber damage in the mdx, mdx/utrn+/- and double knockout (dko) mouse models. We used Masson's trichrome stain and percentage of centrally-nucleated myofibers as indicators of fibrosis and myofiber regeneration, respectively, to assess disease progression in diaphragm and gastrocnemius muscles harvested from young and aged wild-type, mdx, mdx/utrn+/- and dko mice. Our results indicated that eight week-old gastrocnemius muscles of both mdx/utrn+/- and dko hind limb developed fibrosis whereas age-matched mdx gastrocnemius muscle did not (p = 0.002). The amount of collagen found in the mdx/utrn+/- diaphragm was significantly higher than that found in the corresponding diaphragm muscles of wild-type animals, but not of mdx animals (p = 0.0003). Aged mdx/utrn+/- mice developed fibrosis in both diaphragm and gastrocnemius muscles compared to wild-type controls (p = 0.003). Mdx diaphragm was fibrotic in aged mice as well (p = 0.0235), whereas the gastrocnemius muscle in these animals was not fibrotic. We did not measure a significant difference in collagen staining between wild-type and mdx gastrocnemius muscles. The results of this study support previous reports that the moderately-affected mdx/utrn+/- mouse is a better model of DMD, and we show here that this difference is apparent by 2 months of age.