Phenotypic features of genetically modified DMD-XKOXWT pigs
Introduction: Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disorder caused by mutation in the dystrophin gene (DMD) on the X chromosome. Female DMD carriers occasionally exhibit symptoms such as muscle weakness and heart failure. Here, we investigated the characteristics and repre...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Regenerative Therapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352320423000925 |
| _version_ | 1797448046836973568 |
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| author | Kazutoshi Okamoto Hitomi Matsunari Kazuaki Nakano Kazuhiro Umeyama Koki Hasegawa Ayuko Uchikura Shuko Takayanagi Masahito Watanabe Jun Ohgane Michael Stirm Mayuko Kurome Nikolai Klymiuk Masaki Nagaya Eckhard Wolf Hiroshi Nagashima |
| author_facet | Kazutoshi Okamoto Hitomi Matsunari Kazuaki Nakano Kazuhiro Umeyama Koki Hasegawa Ayuko Uchikura Shuko Takayanagi Masahito Watanabe Jun Ohgane Michael Stirm Mayuko Kurome Nikolai Klymiuk Masaki Nagaya Eckhard Wolf Hiroshi Nagashima |
| author_sort | Kazutoshi Okamoto |
| collection | DOAJ |
| description | Introduction: Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disorder caused by mutation in the dystrophin gene (DMD) on the X chromosome. Female DMD carriers occasionally exhibit symptoms such as muscle weakness and heart failure. Here, we investigated the characteristics and representativeness of female DMD carrier (DMD-XKOXWT) pigs as a suitable disease model. Methods: In vitro fertilization using sperm from a DMD-XKOY↔XWTXWT chimeric boar yielded DMD-XKOXWT females, which were used to generate F2 and F3 progeny, including DMD-XKOXWT females. F1–F3 piglets were genotyped and subjected to biochemical analysis for blood creatine kinase (CK), aspartate aminotransferase, and lactate dehydrogenase. Skeletal muscle and myocardial tissue were analyzed for the expression of dystrophin and utrophin, as well as for lymphocyte and macrophage infiltration. Results: DMD-XKOXWT pigs exhibited various characteristics common to human DMD carrier patients, namely, asymptomatic hyperCKemia, dystrophin expression patterns in the skeletal and cardiac muscles, histopathological features of skeletal muscle degeneration, myocardial lesions in adulthood, and sporadic death. Pathological abnormalities observed in the skeletal muscles in DMD-XKOXWT pigs point to a frequent incidence of pathological abnormalities in the musculoskeletal tissues of latent DMD carriers. Our findings suggest a higher risk of myocardial abnormalities in DMD carrier women than previously believed. Conclusions: We demonstrated that DMD-XKOXWT pigs could serve as a suitable large animal model for understanding the pathogenic mechanism in DMD carriers and developing therapies for female DMD carriers. |
| first_indexed | 2024-03-09T14:04:43Z |
| format | Article |
| id | doaj.art-51df675076934a228d6302859f500d01 |
| institution | Directory Open Access Journal |
| issn | 2352-3204 |
| language | English |
| last_indexed | 2024-03-09T14:04:43Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Regenerative Therapy |
| spelling | doaj.art-51df675076934a228d6302859f500d012023-11-30T05:07:53ZengElsevierRegenerative Therapy2352-32042023-12-0124451458Phenotypic features of genetically modified DMD-XKOXWT pigsKazutoshi Okamoto0Hitomi Matsunari1Kazuaki Nakano2Kazuhiro Umeyama3Koki Hasegawa4Ayuko Uchikura5Shuko Takayanagi6Masahito Watanabe7Jun Ohgane8Michael Stirm9Mayuko Kurome10Nikolai Klymiuk11Masaki Nagaya12Eckhard Wolf13Hiroshi Nagashima14Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanLaboratory of Genomic Function Engineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanChair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleissheim, GermanyMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan; Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleissheim, GermanyChair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleissheim, GermanyMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, JapanMeiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan; Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleissheim, GermanyLaboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan; Meiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan; Corresponding author. Laboratory of Biomedical Engineering, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan.Introduction: Duchenne muscular dystrophy (DMD) is a hereditary neuromuscular disorder caused by mutation in the dystrophin gene (DMD) on the X chromosome. Female DMD carriers occasionally exhibit symptoms such as muscle weakness and heart failure. Here, we investigated the characteristics and representativeness of female DMD carrier (DMD-XKOXWT) pigs as a suitable disease model. Methods: In vitro fertilization using sperm from a DMD-XKOY↔XWTXWT chimeric boar yielded DMD-XKOXWT females, which were used to generate F2 and F3 progeny, including DMD-XKOXWT females. F1–F3 piglets were genotyped and subjected to biochemical analysis for blood creatine kinase (CK), aspartate aminotransferase, and lactate dehydrogenase. Skeletal muscle and myocardial tissue were analyzed for the expression of dystrophin and utrophin, as well as for lymphocyte and macrophage infiltration. Results: DMD-XKOXWT pigs exhibited various characteristics common to human DMD carrier patients, namely, asymptomatic hyperCKemia, dystrophin expression patterns in the skeletal and cardiac muscles, histopathological features of skeletal muscle degeneration, myocardial lesions in adulthood, and sporadic death. Pathological abnormalities observed in the skeletal muscles in DMD-XKOXWT pigs point to a frequent incidence of pathological abnormalities in the musculoskeletal tissues of latent DMD carriers. Our findings suggest a higher risk of myocardial abnormalities in DMD carrier women than previously believed. Conclusions: We demonstrated that DMD-XKOXWT pigs could serve as a suitable large animal model for understanding the pathogenic mechanism in DMD carriers and developing therapies for female DMD carriers.http://www.sciencedirect.com/science/article/pii/S2352320423000925DystrophinopathyCarrierDuchenne muscular dystrophyHereditary diseaseLarge animal modelPig |
| spellingShingle | Kazutoshi Okamoto Hitomi Matsunari Kazuaki Nakano Kazuhiro Umeyama Koki Hasegawa Ayuko Uchikura Shuko Takayanagi Masahito Watanabe Jun Ohgane Michael Stirm Mayuko Kurome Nikolai Klymiuk Masaki Nagaya Eckhard Wolf Hiroshi Nagashima Phenotypic features of genetically modified DMD-XKOXWT pigs Regenerative Therapy Dystrophinopathy Carrier Duchenne muscular dystrophy Hereditary disease Large animal model Pig |
| title | Phenotypic features of genetically modified DMD-XKOXWT pigs |
| title_full | Phenotypic features of genetically modified DMD-XKOXWT pigs |
| title_fullStr | Phenotypic features of genetically modified DMD-XKOXWT pigs |
| title_full_unstemmed | Phenotypic features of genetically modified DMD-XKOXWT pigs |
| title_short | Phenotypic features of genetically modified DMD-XKOXWT pigs |
| title_sort | phenotypic features of genetically modified dmd xkoxwt pigs |
| topic | Dystrophinopathy Carrier Duchenne muscular dystrophy Hereditary disease Large animal model Pig |
| url | http://www.sciencedirect.com/science/article/pii/S2352320423000925 |
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