title: Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy.
abstract: 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. Lmod3(PB/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.
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: You
authors.affiliation: 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.
authors.forename: Tong-ruei
authors.initials: TR
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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 lingsun@fudan.edu.cn tian.xu@yale.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: Sun
authors.affiliation: 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 lingsun@fudan.edu.cn tian.xu@yale.edu.
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
mesh_terms: D000818:Animals; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000172:deficiency* / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000473:pathology*; D018908:Muscle Weakness / Q000150:complications / Q000473:pathology; D009133:Muscular Atrophy / Q000150:complications / Q000473:pathology*; D017696:Myopathies, Nemaline / Q000150:complications / Q000473:pathology*; D012518:Sarcomeres / Q000473:pathology
chemical_list: D008840:Microfilament Proteins; C000598980:leiomodin-3 protein, mouse
keywords: Fast-myofiber atrophy; Leiomodin-3; Mouse; Nemaline myopathy