Functional cardiac consequences of β-adrenergic stress-induced injury in a model of Duchenne muscular dystrophy.

IF 4 3区 医学 Q2 CELL BIOLOGY Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-09 DOI:10.1242/dmm.050852
Conner C Earl, Areli J Javier, Alyssa M Richards, Larry W Markham, Craig J Goergen, Steven S Welc
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Abstract

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD); however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to stimulate injury and enhance cardiac pathology in the mdx model, many methods lead to high mortality with variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. mdx and wild-type mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathological assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes and diminished cardiac reserve in mdx compared to wild-type mice. Our findings highlight the utility of challenging mdx mice with low-dose isoproterenol as a valuable model for exploring therapies targeting DMD-associated cardiac pathologies.

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在杜氏肌营养不良症 mdx 小鼠模型中,β 肾上腺素能应激诱导损伤对心脏功能的影响。
心肌病是杜氏肌营养不良症(DMD)的主要死因,然而,在 DMD 的 mdx 小鼠模型中,心脏表型与 DMD 相关心肌病不同。虽然有人利用药理应激刺激 mdx 模型中的损伤并增强心脏病理,但许多方法都会导致高死亡率和多变的心脏结果,而且不能再现人类疾病中的心脏结构和功能变化。在此,我们介绍一种简单有效的方法,利用先进的二维和四维高频超声监测体内心脏功能障碍的进展,从而增强 mdx 小鼠的心脏表型模型。在我们的研究中,mdx 小鼠和野生型(WT)小鼠每天接受低剂量(2 毫克/千克/天)异丙肾上腺素注射,为期 10 天。组织病理学评估显示,异丙托品醇治疗加重了 mdx 小鼠的心肌细胞损伤、升高了血清心肌肌钙蛋白 I 水平并加剧了纤维化。超声波显示,与野生型相比,mdx 小鼠的心室功能减退、室壁厚度减少、体积增大,心脏储备功能减弱。我们的研究结果凸显了用低剂量异丙肾上腺素挑战 mdx 小鼠作为探索针对 DMD 相关心脏病理的疗法的宝贵模型的实用性。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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