Cardiac lesions in Duchenne muscular dystrophy model rats with out-of-frame Dmd gene mutation mediated by CRISPR/Cas9 system

Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by X-chromosomal DMD 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 a...

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Veröffentlicht in:Journal of Toxicologic Pathology 2020, Vol.33(4), pp.227-236
Hauptverfasser: Miyamoto, Mao, Tochinai, Ryota, Sekizawa, Shin-ich, Shiga, Takanori, Uchida, Kazuyuki, Tsuru, Yoshiharu, Kuwahara, Masayoshi
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container_issue 4
container_start_page 227
container_title Journal of Toxicologic Pathology
container_volume 33
creator Miyamoto, Mao
Tochinai, Ryota
Sekizawa, Shin-ich
Shiga, Takanori
Uchida, Kazuyuki
Tsuru, Yoshiharu
Kuwahara, Masayoshi
description Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by X-chromosomal DMD 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, Dmd-mutated rats (W-Dmdem1Kykn) were obtained. Dmd 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.
doi_str_mv 10.1293/tox.2020-0018
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(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. 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(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. 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Tochinai, Ryota ; Sekizawa, Shin-ich ; Shiga, Takanori ; Uchida, Kazuyuki ; Tsuru, Yoshiharu ; Kuwahara, Masayoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c542t-c772a919837c1b0fe47dba72ceb274e7dc3830cad6c7bfd5f757153e8f3e70043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Age</topic><topic>Aging</topic><topic>Amplitudes</topic><topic>arrhythmia</topic><topic>cardiac necrosis</topic><topic>Cardiology</topic><topic>Cardiomyocytes</topic><topic>Contraction</topic><topic>CRISPR</topic><topic>Degeneration</topic><topic>Duchenne's muscular dystrophy</topic><topic>Dystrophin</topic><topic>Dystrophy</topic><topic>echocardiogram</topic><topic>Echocardiography</topic><topic>EKG</topic><topic>electrocardiogram</topic><topic>Electrocardiography</topic><topic>Fibrosis</topic><topic>Heart</topic><topic>Intervals</topic><topic>Lesions</topic><topic>Muscular dystrophy</topic><topic>Mutation</topic><topic>Necrosis</topic><topic>Offspring</topic><topic>Original</topic><topic>P waves</topic><topic>Point mutation</topic><topic>Sclerosis</topic><topic>Ventricle</topic><toplevel>online_resources</toplevel><creatorcontrib>Miyamoto, Mao</creatorcontrib><creatorcontrib>Tochinai, Ryota</creatorcontrib><creatorcontrib>Sekizawa, Shin-ich</creatorcontrib><creatorcontrib>Shiga, Takanori</creatorcontrib><creatorcontrib>Uchida, Kazuyuki</creatorcontrib><creatorcontrib>Tsuru, Yoshiharu</creatorcontrib><creatorcontrib>Kuwahara, Masayoshi</creatorcontrib><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of Toxicologic Pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miyamoto, Mao</au><au>Tochinai, Ryota</au><au>Sekizawa, Shin-ich</au><au>Shiga, Takanori</au><au>Uchida, Kazuyuki</au><au>Tsuru, Yoshiharu</au><au>Kuwahara, Masayoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cardiac lesions in Duchenne muscular dystrophy model rats with out-of-frame Dmd gene mutation mediated by CRISPR/Cas9 system</atitle><jtitle>Journal of Toxicologic Pathology</jtitle><addtitle>J Toxicol Pathol</addtitle><date>2020-01-01</date><risdate>2020</risdate><volume>33</volume><issue>4</issue><spage>227</spage><epage>236</epage><pages>227-236</pages><issn>0914-9198</issn><eissn>1881-915X</eissn><eissn>1347-7404</eissn><abstract>Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by X-chromosomal DMD 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, Dmd-mutated rats (W-Dmdem1Kykn) were obtained. Dmd 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.</abstract><cop>Tokyo</cop><pub>JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY</pub><pmid>33239841</pmid><doi>10.1293/tox.2020-0018</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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subjects Age
Aging
Amplitudes
arrhythmia
cardiac necrosis
Cardiology
Cardiomyocytes
Contraction
CRISPR
Degeneration
Duchenne's muscular dystrophy
Dystrophin
Dystrophy
echocardiogram
Echocardiography
EKG
electrocardiogram
Electrocardiography
Fibrosis
Heart
Intervals
Lesions
Muscular dystrophy
Mutation
Necrosis
Offspring
Original
P waves
Point mutation
Sclerosis
Ventricle
title Cardiac lesions in Duchenne muscular dystrophy model rats with out-of-frame Dmd gene mutation mediated by CRISPR/Cas9 system
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