Cardiac Lesions in Duchenne Muscular Dystrophy Model Rats with Out-of-frame Gene Mutation Mediated by CRISPR/Cas9 System

Overview

Journal J Toxicol Pathol

Date 2020 Nov 26

PMID 33239841

Citations 4

Authors

Mao Miyamoto

Ryota Tochinai

Shin-Ich Sekizawa

Takanori Shiga

Kazuyuki Uchida

Yoshiharu Tsuru

Masayoshi Kuwahara

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Ivabradine ameliorates cardiomyopathy progression in a Duchenne muscular dystrophy model rat.

Tochinai R, Kimura K, Saika T, Fujii W, Morita H, Nakanishi K Exp Anim. 2023; 73(2):145-153.

PMID: 37914289 PMC: 11091361. DOI: 10.1538/expanim.23-0087.

A medium-chain triglyceride containing ketogenic diet exacerbates cardiomyopathy in a CRISPR/Cas9 gene-edited rat model with Duchenne muscular dystrophy.

Fujikura Y, Kimura K, Yamanouchi K, Sugihara H, Hatakeyama M, Zhuang H Sci Rep. 2022; 12(1):11580.

PMID: 35803994 PMC: 9270409. DOI: 10.1038/s41598-022-15934-9.

Dystrophin gene editing by CRISPR/Cas9 system in human skeletal muscle cell line (HSkMC).

Dara M, Razban V, Mazloomrezaei M, Ranjbar M, Nourigorji M, Dianatpour M Iran J Basic Med Sci. 2021; 24(8):1153-1158.

PMID: 34804433 PMC: 8591754. DOI: 10.22038/IJBMS.2021.54711.12269.

Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy.

Gowran A, Brioschi M, Rovina D, Chiesa M, Piacentini L, Mallia S Int J Mol Sci. 2021; 22(16).

PMID: 34445659 PMC: 8396646. DOI: 10.3390/ijms22168954.

References

Branco D, Wolf C, Sherwood M, Hammer P, Kang P, Berul C . Cardiac electrophysiological characteristics of the mdx ( 5cv ) mouse model of Duchenne muscular dystrophy. J Interv Card Electrophysiol. 2007; 20(1-2):1-7. DOI: 10.1007/s10840-007-9168-z. View

Villa C, Czosek R, Ahmed H, Khoury P, Anderson J, Knilans T . Ambulatory Monitoring and Arrhythmic Outcomes in Pediatric and Adolescent Patients With Duchenne Muscular Dystrophy. J Am Heart Assoc. 2016; 5(1). PMC: 4859379. DOI: 10.1161/JAHA.115.002620. View

Masubuchi N, Shidoh Y, Kondo S, Takatoh J, Hanaoka K . Subcellular localization of dystrophin isoforms in cardiomyocytes and phenotypic analysis of dystrophin-deficient mice reveal cardiac myopathy is predominantly caused by a deficiency in full-length dystrophin. Exp Anim. 2013; 62(3):211-7. PMC: 4160940. DOI: 10.1538/expanim.62.211. View

Megeney L, Kablar B, Perry R, Ying C, May L, Rudnicki M . Severe cardiomyopathy in mice lacking dystrophin and MyoD. Proc Natl Acad Sci U S A. 1999; 96(1):220-5. PMC: 15120. DOI: 10.1073/pnas.96.1.220. View

Thomas T, Morgan T, Burnette W, Markham L . Correlation of heart rate and cardiac dysfunction in Duchenne muscular dystrophy. Pediatr Cardiol. 2012; 33(7):1175-9. DOI: 10.1007/s00246-012-0281-0. View

Kieny P, Chollet S, Delalande P, Le Fort M, Magot A, Pereon Y . Evolution of life expectancy of patients with Duchenne muscular dystrophy at AFM Yolaine de Kepper centre between 1981 and 2011. Ann Phys Rehabil Med. 2013; 56(6):443-54. DOI: 10.1016/j.rehab.2013.06.002. View

Tochinai R, Nagata Y, Ando M, Hata C, Suzuki T, Asakawa N . Combretastatin A4 disodium phosphate-induced myocardial injury. J Toxicol Pathol. 2016; 29(3):163-71. PMC: 4963615. DOI: 10.1293/tox.2016-0012. View

Banks G, Chamberlain J . The value of mammalian models for duchenne muscular dystrophy in developing therapeutic strategies. Curr Top Dev Biol. 2009; 84:431-53. DOI: 10.1016/S0070-2153(08)00609-1. View

Chu V, Otero J, Lopez O, Sullivan M, Morgan J, Amende I . Electrocardiographic findings in mdx mice: a cardiac phenotype of Duchenne muscular dystrophy. Muscle Nerve. 2002; 26(4):513-9. DOI: 10.1002/mus.10223. View

10.

Nigro G, Comi L, Politano L, Bain R . The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol. 1990; 26(3):271-7. DOI: 10.1016/0167-5273(90)90082-g. View

11.

Petrof B, Shrager J, Stedman H, Kelly A, Sweeney H . Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A. 1993; 90(8):3710-4. PMC: 46371. DOI: 10.1073/pnas.90.8.3710. View

12.

Lanza G, Dello Russo A, Giglio V, De Luca L, Messano L, Santini C . Impairment of cardiac autonomic function in patients with Duchenne muscular dystrophy: relationship to myocardial and respiratory function. Am Heart J. 2001; 141(5):808-12. DOI: 10.1067/mhj.2001.114804. View

13.

Torres L, DUCHEN L . The mutant mdx: inherited myopathy in the mouse. Morphological studies of nerves, muscles and end-plates. Brain. 1987; 110 ( Pt 2):269-99. DOI: 10.1093/brain/110.2.269. View

14.

Finder J, Birnkrant D, Carl J, Farber H, Gozal D, Iannaccone S . Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med. 2004; 170(4):456-65. DOI: 10.1164/rccm.200307-885ST. View

15.

Segawa K, Komaki H, Mori-Yoshimura M, Oya Y, Kimura K, Tachimori H . Cardiac conduction disturbances and aging in patients with Duchenne muscular dystrophy. Medicine (Baltimore). 2017; 96(42):e8335. PMC: 5662415. DOI: 10.1097/MD.0000000000008335. View

16.

Sengupta P . The Laboratory Rat: Relating Its Age With Human's. Int J Prev Med. 2013; 4(6):624-30. PMC: 3733029. View

17.

Chiang D, Allen H, Kim J, Valdes S, Wang Y, Pignatelli R . Relation of Cardiac Dysfunction to Rhythm Abnormalities in Patients With Duchenne or Becker Muscular Dystrophies. Am J Cardiol. 2016; 117(8):1349-54. DOI: 10.1016/j.amjcard.2016.01.031. View

18.

Larcher T, Lafoux A, Tesson L, Remy S, Thepenier V, Francois V . Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy. PLoS One. 2014; 9(10):e110371. PMC: 4195719. DOI: 10.1371/journal.pone.0110371. View

19.

Wells D . Tracking progress: an update on animal models for Duchenne muscular dystrophy. Dis Model Mech. 2018; 11(6). PMC: 6031358. DOI: 10.1242/dmm.035774. View

20.

Tochinai R, Komatsu K, Murakami J, Nagata Y, Ando M, Hata C . Histopathological and functional changes in a single-dose model of combretastatin A4 disodium phosphate-induced myocardial damage in rats. J Toxicol Pathol. 2018; 31(4):307-313. PMC: 6206283. DOI: 10.1293/tox.2018-0023. View