Mineralocorticoid Receptor Antagonists in Muscular Dystrophy Mice During Aging and Exercise.
Mineralocorticoid Receptor Antagonists in Muscular Dystrophy Mice During Aging and Exercise.
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DOI：
10.3233/jnd-180323
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发表时间：
2018-01-01
影响因子：
3.3
通讯作者：
Janssen, Paul M L
中科院分区：
文献类型：
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作者：
Lowe, Jeovanna;Kadakia, Feni K;Janssen, Paul M L
背景：在血管紧张素转换酶抑制剂中加入矿化皮质激素受体拮抗剂已显示出对久坐不动的mdx小鼠骨骼肌和心肌结果的临床前疗效，mdx是一种杜氏肌营养不良（DMD）模型。mdx基因型DMD模型病理轻微，在基线时难以区分非治愈性治疗效果。由于矿皮质激素受体拮抗剂的心脏益处已经转化为DMD患者，因此通过进一步确定疗效参数来优化骨骼肌的潜在优势是很重要的。目的：我们的目的是通过三种不同的加重mdx表型的报道方法来测试是否可以检测到矿化皮质激素受体拮抗剂加入血管紧张素转换酶抑制剂的治疗效果。方法：我们在10周龄运动、1岁久坐和5月龄异丙肾上腺素治疗的mdx小鼠中测试了赖诺普利和矿物皮质激素受体拮抗剂旋内酯的治疗效果，并进行了全面的功能和组织学测量。结果：没有一种加重mdx表型的方案导致病理显著增强，也没有观察到治疗的显著益处。结论：由于营养不良肌肉免疫细胞内源性矿化皮质激素醛固酮的产生可以解释拮抗剂的疗效，这些药物可能在mdx小鼠炎症高峰的窄窗口期发挥最佳作用。运动和年老的mdx小鼠没有表现出大量的损伤和炎症，这可能解释了这些药物缺乏持续功效。由于炎症在DMD患者中更为普遍，因此矿皮质激素受体拮抗剂在患者中的治疗窗口期可能更长。
BACKGROUND: Mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors have shown preclinical efficacy for both skeletal and cardiac muscle outcomes in young sedentary dystrophin-deficient mdx mice also haploinsufficient for utrophin, a Duchenne muscular dystrophy (DMD) model. The mdx genotypic DMD model has mild pathology, making non-curative therapeutic effects difficult to distinguish at baseline. Since the cardiac benefit of mineralocorticoid receptor antagonists has been translated to DMD patients, it is important to optimize potential advantages for skeletal muscle by further defining efficacy parameters.OBJECTIVE: We aimed to test whether therapeutic effects of mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors are detectable using three different reported methods of exacerbating the mdx phenotype.METHODS: We tested treatment with lisinopril and the mineralocorticoid receptor antagonist spironolactone in: 10 week-old exercised, 1 year-old sedentary, and 5 month-old isoproterenol treated mdx mice and performed comprehensive functional and histological measurements.RESULTS: None of the protocols to exacerbate mdx phenotypes resulted in dramatically enhanced pathology and no significant benefit was observed with treatment.CONCLUSIONS: Since endogenous mineralocorticoid aldosterone production from immune cells in dystrophic muscle may explain antagonist efficacy, it is likely that these drugs work optimally during the narrow window of peak inflammation in mdx mice. Exercised and aged mdx mice do not display prolific damage and inflammation, likely explaining the absence of continued efficacy of these drugs. Since inflammation is more prevalent in DMD patients, the therapeutic window for mineralocorticoid receptor antagonists in patients may be longer.