Diaphragm rescue alone prevents heart dysfunction in dystrophic mice
Diaphragm rescue alone prevents heart dysfunction in dystrophic mice
复制标题
仅隔膜救援可预防营养不良小鼠的心脏功能障碍
DOI：
10.1093/hmg/ddq477
复制
发表时间：
2011-02-01
影响因子：
3.5
通讯作者：
Wood, Matthew J. A.
中科院分区：
文献类型：
--
作者：
Crisp, Alastair;Yin, HaiFang;Wood, Matthew J. A.
Duchenne肌营养不良症(DMD)是一种X连锁的隐性遗传病，在大多数情况下，由427 kDa的细胞骨架蛋白dystrophin完全缺失引起。没有有效的治疗方法，受影响的人在30岁前死于呼吸衰竭和心肌病。在这里，我们研究了在DMD动物模型中，是否可以通过增加横隔膜utroin或dystrophin的表达从而恢复横隔膜的功能来预防心肌病。在一只转基因MDX小鼠中，utroin在骨骼肌和横隔膜中过度表达，但在心脏中不表达，我们发现心脏功能，特别是使用活体磁共振成像测量的右和左室射血分数，恢复到了野生型水平。在MDX小鼠中，使用多肽连接的磷二酸酯吗啡低聚物(PPMO)治疗后，只有骨骼肌和横隔肌中的Dstrophin水平得到了高水平的恢复，心功能也恢复到了野生水平。在Dstrophin/utroin缺陷双基因敲除(DKO)小鼠(一种受影响更严重的DMD动物模型)中，PPMO治疗再次仅在骨骼肌和横隔肌产生高水平的dystrophin，并再次将心功能恢复到野生型水平。在dKO小鼠中，横隔膜加心脏的治疗和单独横隔膜的治疗在心功能方面没有差别。无论使用何种方法，恢复横隔膜和其他呼吸肌功能足以预防营养不良小鼠的心肌病。这一治疗营养不良小鼠呼吸肌以预防心肌病的新机制值得进一步研究，因为它意味着需要直接治疗DMD的心脏。
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused, in most cases, by the complete absence of the 427 kDa cytoskeletal protein, dystrophin. There is no effective treatment, and affected individuals die from respiratory failure and cardiomyopathy by age 30. Here, we investigated whether cardiomyopathy could be prevented in animal models of DMD by increasing diaphragm utrophin or dystrophin expression and thereby restoring diaphragm function. In a transgenic mdx mouse, where utrophin was over expressed in the skeletal muscle and the diaphragm, but not in the heart, we found cardiac function, specifically right and left ventricular ejection fraction as measured using in vivo magnetic resonance imaging, was restored to wild-type levels. In mdx mice treated with a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that resulted in high levels of dystrophin restoration in the skeletal muscle and the diaphragm only, cardiac function was also restored to wild-type levels. In dystrophin/utrophin-deficient double-knockout (dKO) mice, a more severely affected animal model of DMD, treatment with a PPMO again produced high levels of dystrophin only in the skeletal muscle and the diaphragm, and once more restored cardiac function to wild-type levels. In the dKO mouse, there was no difference in heart function between treatment of the diaphragm plus the heart and treatment of the diaphragm alone. Restoration of diaphragm and other respiratory muscle function, irrespective of the method used, was sufficient to prevent cardiomyopathy in dystrophic mice. This novel mechanism of treating respiratory muscles to prevent cardiomyopathy in dystrophic mice warrants further investigation for its implications on the need to directly treat the heart in DMD.