Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy
Nemaline myopathy (NM) is one of the most common forms of congenital myopathy, and affects either fast myofibers, slow myofibers, or both. However, an animal model for congenital myopathy with fast-myofiber-specific atrophy is not available. Furthermore, mutations in the leiomodin-3 (LMOD3) gene hav...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2015-06-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/8/6/635 |
| _version_ | 1818952181938651136 |
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| author | Lei Tian Sheng Ding Yun You Tong-ruei Li Yan Liu Xiaohui Wu Ling Sun Tian Xu |
| author_facet | Lei Tian Sheng Ding Yun You Tong-ruei Li Yan Liu Xiaohui Wu Ling Sun Tian Xu |
| author_sort | Lei Tian |
| collection | DOAJ |
| description | Nemaline myopathy (NM) is one of the most common forms of congenital myopathy, and affects either fast myofibers, slow myofibers, or both. However, an animal model for congenital myopathy with fast-myofiber-specific atrophy is not available. Furthermore, mutations in the leiomodin-3 (LMOD3) gene have recently been identified in a group of individuals with NM. However, it is not clear how loss of LMOD3 leads to NM. Here, we report a mouse mutant in which the piggyBac (PB) transposon is inserted into the Lmod3 gene and disrupts its expression. Lmod3PB/PB mice show severe muscle weakness and postnatal growth retardation. Electron microscopy and immunofluorescence studies of the mutant skeletal muscles revealed the presence of nemaline bodies, a hallmark of NM, and disorganized sarcomeric structures. Interestingly, Lmod3 deficiency caused muscle atrophy specific to the fast fibers. Together, our results show that Lmod3 is required in the fast fibers for sarcomere integrity, and this study offers the first NM mouse model with muscle atrophy that is specific to fast fibers. This model could be a valuable resource for interrogating myopathy pathogenesis and developing therapeutics for NM as well as other pathophysiological conditions with preferential atrophy of fast fibers, including cancer cachexia and sarcopenia. |
| first_indexed | 2024-12-20T09:46:18Z |
| format | Article |
| id | doaj.art-8599357c3a404958b416478586fed9e1 |
| institution | Directory Open Access Journal |
| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-20T09:46:18Z |
| publishDate | 2015-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-8599357c3a404958b416478586fed9e12022-12-21T19:44:44ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032015-06-018663564110.1242/dmm.019430019430Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophyLei Tian0Sheng Ding1Yun You2Tong-ruei Li3Yan Liu4Xiaohui Wu5Ling Sun6Tian Xu7 State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT 06536, USA State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China Nemaline myopathy (NM) is one of the most common forms of congenital myopathy, and affects either fast myofibers, slow myofibers, or both. However, an animal model for congenital myopathy with fast-myofiber-specific atrophy is not available. Furthermore, mutations in the leiomodin-3 (LMOD3) gene have recently been identified in a group of individuals with NM. However, it is not clear how loss of LMOD3 leads to NM. Here, we report a mouse mutant in which the piggyBac (PB) transposon is inserted into the Lmod3 gene and disrupts its expression. Lmod3PB/PB mice show severe muscle weakness and postnatal growth retardation. Electron microscopy and immunofluorescence studies of the mutant skeletal muscles revealed the presence of nemaline bodies, a hallmark of NM, and disorganized sarcomeric structures. Interestingly, Lmod3 deficiency caused muscle atrophy specific to the fast fibers. Together, our results show that Lmod3 is required in the fast fibers for sarcomere integrity, and this study offers the first NM mouse model with muscle atrophy that is specific to fast fibers. This model could be a valuable resource for interrogating myopathy pathogenesis and developing therapeutics for NM as well as other pathophysiological conditions with preferential atrophy of fast fibers, including cancer cachexia and sarcopenia.http://dmm.biologists.org/content/8/6/635Leiomodin-3Nemaline myopathyMouseFast-myofiber atrophy |
| spellingShingle | Lei Tian Sheng Ding Yun You Tong-ruei Li Yan Liu Xiaohui Wu Ling Sun Tian Xu Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy Disease Models & Mechanisms Leiomodin-3 Nemaline myopathy Mouse Fast-myofiber atrophy |
| title | Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy |
| title_full | Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy |
| title_fullStr | Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy |
| title_full_unstemmed | Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy |
| title_short | Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy |
| title_sort | leiomodin 3 deficient mice display nemaline myopathy with fast myofiber atrophy |
| topic | Leiomodin-3 Nemaline myopathy Mouse Fast-myofiber atrophy |
| url | http://dmm.biologists.org/content/8/6/635 |
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