Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment.
Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment.
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DOI：
10.1093/hmg/ddy346
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发表时间：
2019-02-01
影响因子：
3.5
通讯作者：
Wood MJ
中科院分区：
文献类型：
--
作者：
Betts CA;McClorey G;Healicon R;Hammond SM;Manzano R;Muses S;Ball V;Godfrey C;Merritt TM;van Westering T;O'Donovan L;Wells KE;Gait MJ;Wells DJ;Tyler D;Wood MJ
杜氏肌营养不良症（DMD）是由肌营养不良蛋白的丢失引起的，导致进行性肌无力和由于呼吸和/或心脏并发症而过早死亡。心脏受累的特征是进行性扩张型心肌病、短轴缩短率降低和代谢功能障碍，包括主要心脏代谢底物脂肪酸代谢减少。已经开发了几种小鼠模型来研究抗肌萎缩蛋白缺乏的分子和病理学后果，但不能概括人类疾病病理学的所有方面，并表现出轻度的心脏表型。在这里，我们证明，Cmah（胞苷一磷酸-唾液酸羟化酶）缺陷mdx小鼠（Cmah−/−;mdx）有一个加速心脏表型相比，已建立的mdx模型。Cmah−/−;与mdx小鼠相比，mdx小鼠显示出更早的功能恶化，特别是在12周龄时右心室（RV）射血分数和每搏输出量（SV）的降低，以及在24周龄时左心室舒张容积的降低，随后SV降低。它们进一步显示了纤维化（Ctgf）、氧化损伤（Nox 4）和血液动力学负荷（Nppa）的心脏损伤标志物的早期升高。使用超极化磁共振波谱法评估心脏代谢底物需求，表明Cmah−/−;mdx小鼠体内糖酵解通量增加。线粒体基因（Ucp 3和Cpt 1）的早期上调和关键糖酵解基因（Pdk 1、Pdk 4、Ppara）的下调也表明Cmah−/−;mdx小鼠的心脏代谢紊乱，并向葡萄糖利用转变。此外，我们显示用肽缀合的外显子跳跃反义寡核苷酸（20周方案）长期治疗，导致20%的心脏肌营养不良蛋白蛋白恢复，并显著改善RV心脏功能。因此，Cmah−/−;mdx小鼠代表了用于评估新型DMD疗法的心脏益处的适当模型。
Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin protein, leading to progressive muscle weakness and premature death due to respiratory and/or cardiac complications. Cardiac involvement is characterized by progressive dilated cardiomyopathy, decreased fractional shortening and metabolic dysfunction involving reduced metabolism of fatty acids—the major cardiac metabolic substrate. Several mouse models have been developed to study molecular and pathological consequences of dystrophin deficiency, but do not recapitulate all aspects of human disease pathology and exhibit a mild cardiac phenotype. Here we demonstrate that Cmah (cytidine monophosphate-sialic acid hydroxylase)-deficient mdx mice (Cmah−/−;mdx) have an accelerated cardiac phenotype compared to the established mdx model. Cmah−/−;mdx mice display earlier functional deterioration, specifically a reduction in right ventricle (RV) ejection fraction and stroke volume (SV) at 12 weeks of age and decreased left ventricle diastolic volume with subsequent reduced SV compared to mdx mice by 24 weeks. They further show earlier elevation of cardiac damage markers for fibrosis (Ctgf), oxidative damage (Nox4) and haemodynamic load (Nppa). Cardiac metabolic substrate requirement was assessed using hyperpolarized magnetic resonance spectroscopy indicating increased in vivo glycolytic flux in Cmah−/−;mdx mice. Early upregulation of mitochondrial genes (Ucp3 and Cpt1) and downregulation of key glycolytic genes (Pdk1, Pdk4, Ppara), also denote disturbed cardiac metabolism and shift towards glucose utilization in Cmah−/−;mdx mice. Moreover, we show long-term treatment with peptide-conjugated exon skipping antisense oligonucleotides (20-week regimen), resulted in 20% cardiac dystrophin protein restoration and significantly improved RV cardiac function. Therefore, Cmah−/−;mdx mice represent an appropriate model for evaluating cardiac benefit of novel DMD therapeutics.
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DOI：
10.1038/mtna.2012.30
发表时间：
2012-08-14
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.4
作者：
Dodd, Michael S.;Ball, Vicky;Tyler, Damian J.
通讯作者：
Tyler, Damian J.
影响因子：
1.6
作者：
Kirchmann, C;Kececioglu, D;Dittrich, S
通讯作者：
Dittrich, S
影响因子：
2.8
作者：
Eagle, M;Baudouin, SV;Bushby, K
通讯作者：
Bushby, K
影响因子：
3.4
作者：
Holland, Ashling;Dowling, Paul;Ohlendieck, Kay
通讯作者：
Ohlendieck, Kay