Miyamoto Mao, Tochinai Ryota, Sekizawa Shin-Ich, Shiga Takanori, Uchida Kazuyuki, Tsuru Yoshiharu, Kuwahara Masayoshi
Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
J Toxicol Pathol. 2020 Oct;33(4):227-236. doi: 10.1293/tox.2020-0018. Epub 2020 Jul 31.
Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by X-chromosomal gene mutations. Recently, a new CRISPR/Cas9-mediated DMD rat model (cDMDR) was established and is expected to show cardiac lesions similar to those in humans. We therefore investigated the pathological and pathophysiological features of the cardiac lesions and their progression in cDMDR. For our cDMDR, -mutated rats (W-Dmd ) were obtained. heterozygous-deficient females and wild-type (WT) males were mated, and male offspring including WT as controls were used. (1) Hearts were collected at 3, 5, and 10 months of age, and HE- and Masson's trichrome-stained specimens were observed. (2) Electrocardiogram (ECG) recordings were made and analyzed at 3, 5, and 8 months of age. (3) Echocardiography was performed at 9 months of age. In cDMDR rats, (1) degeneration/necrosis of cardiomyocytes and myocardial fibrosis prominent in the right ventricular wall and the outer layer of the left ventricular wall were observed. Fibrosis became more prominent with aging. (2) Lower P wave amplitudes and greater R wave amplitudes were detected. PR intervals tended to be shorter. QT intervals were longer at 3 months but tended to be shorter at 8 months. Sinus irregularity and premature ventricular contraction were observed at 8 months. (3) Echocardiography indicated myocardial sclerosis and a tendency of systolic dysfunction. Pathological and pathophysiological changes occurred in cDMDR rat hearts and progressed with aging, which is, to some extent, similar to what occurs in humans. Thus, cDMDR could be a valuable model for studying cardiology of human DMD.
杜氏肌营养不良症（DMD）是一种由X染色体基因突变引起的进行性肌肉疾病。最近，一种新的CRISPR/Cas9介导的DMD大鼠模型（cDMDR）被建立起来，预计该模型会出现与人类相似的心脏病变。因此，我们研究了cDMDR中心脏病变的病理和病理生理特征及其进展情况。对于我们的cDMDR，获得了 - 突变大鼠（W-Dmd ）。将杂合子缺陷雌性大鼠与野生型（WT）雄性大鼠交配，并使用包括WT作为对照的雄性后代。（1）在3、5和10月龄时采集心脏，观察苏木精 - 伊红（HE）和马松三色染色标本。（2）在3、5和8月龄时进行心电图（ECG）记录并分析。（3）在9月龄时进行超声心动图检查。在cDMDR大鼠中，（1）观察到心肌细胞变性/坏死以及右心室壁和左心室壁外层的心肌纤维化明显。纤维化随着年龄增长而更加明显。（2）检测到较低的P波振幅和较高的R波振幅。PR间期倾向于较短。QT间期在3个月时较长，但在8个月时倾向于较短。在8个月时观察到窦性心律不齐和室性早搏。（3）超声心动图显示心肌硬化和收缩功能障碍的趋势。cDMDR大鼠心脏发生了病理和病理生理变化，并随着年龄增长而进展，这在一定程度上与人类发生的情况相似。因此，cDMDR可能是研究人类DMD心脏病学的有价值模型。
