Natural history of a mouse model of X-linked myotubular myopathy
X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss-of-expression/function mutations in the myotubularin (MTM1) gene. Much of what is known about the disease, as well as the treatment strategies, has been uncovered through experimentatio...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-07-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/15/7/dmm049342 |
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| author | Ege Sarikaya Nesrin Sabha Jonathan Volpatti Emanuela Pannia Nika Maani Hernan D. Gonorazky Alper Celik Yijng Liang Paula Onofre-Oliveira James J. Dowling |
| author_facet | Ege Sarikaya Nesrin Sabha Jonathan Volpatti Emanuela Pannia Nika Maani Hernan D. Gonorazky Alper Celik Yijng Liang Paula Onofre-Oliveira James J. Dowling |
| author_sort | Ege Sarikaya |
| collection | DOAJ |
| description | X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss-of-expression/function mutations in the myotubularin (MTM1) gene. Much of what is known about the disease, as well as the treatment strategies, has been uncovered through experimentation in pre-clinical models, particularly the Mtm1 gene knockout mouse line (Mtm1 KO). Despite this understanding, and the identification of potential therapies, much remains to be understood about XLMTM disease pathomechanisms, and about the normal functions of MTM1 in muscle development. To lay the groundwork for addressing these knowledge gaps, we performed a natural history study of Mtm1 KO mice. This included longitudinal comparative analyses of motor phenotype, transcriptome and proteome profiles, muscle structure and targeted molecular pathways. We identified age-associated changes in gene expression, mitochondrial function, myofiber size and key molecular markers, including DNM2. Importantly, some molecular and histopathologic changes preceded overt phenotypic changes, while others, such as triad structural alternations, occurred coincidentally with the presence of severe weakness. In total, this study provides a comprehensive longitudinal evaluation of the murine XLMTM disease process, and thus provides a critical framework for future investigations. |
| first_indexed | 2024-04-11T21:22:43Z |
| format | Article |
| id | doaj.art-00e21e3cffdc4d9fbf0a56fd56b7ca81 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-11T21:22:43Z |
| publishDate | 2022-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-00e21e3cffdc4d9fbf0a56fd56b7ca812022-12-22T04:02:32ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-07-0115710.1242/dmm.049342049342Natural history of a mouse model of X-linked myotubular myopathyEge Sarikaya0Nesrin Sabha1Jonathan Volpatti2Emanuela Pannia3Nika Maani4Hernan D. Gonorazky5Alper Celik6Yijng Liang7Paula Onofre-Oliveira8James J. Dowling9 Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Division of Neurology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Centre for Computational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Centre for Computational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss-of-expression/function mutations in the myotubularin (MTM1) gene. Much of what is known about the disease, as well as the treatment strategies, has been uncovered through experimentation in pre-clinical models, particularly the Mtm1 gene knockout mouse line (Mtm1 KO). Despite this understanding, and the identification of potential therapies, much remains to be understood about XLMTM disease pathomechanisms, and about the normal functions of MTM1 in muscle development. To lay the groundwork for addressing these knowledge gaps, we performed a natural history study of Mtm1 KO mice. This included longitudinal comparative analyses of motor phenotype, transcriptome and proteome profiles, muscle structure and targeted molecular pathways. We identified age-associated changes in gene expression, mitochondrial function, myofiber size and key molecular markers, including DNM2. Importantly, some molecular and histopathologic changes preceded overt phenotypic changes, while others, such as triad structural alternations, occurred coincidentally with the presence of severe weakness. In total, this study provides a comprehensive longitudinal evaluation of the murine XLMTM disease process, and thus provides a critical framework for future investigations.http://dmm.biologists.org/content/15/7/dmm049342micemyotubularinmyotubular myopathymuscle diseasenatural history |
| spellingShingle | Ege Sarikaya Nesrin Sabha Jonathan Volpatti Emanuela Pannia Nika Maani Hernan D. Gonorazky Alper Celik Yijng Liang Paula Onofre-Oliveira James J. Dowling Natural history of a mouse model of X-linked myotubular myopathy Disease Models & Mechanisms mice myotubularin myotubular myopathy muscle disease natural history |
| title | Natural history of a mouse model of X-linked myotubular myopathy |
| title_full | Natural history of a mouse model of X-linked myotubular myopathy |
| title_fullStr | Natural history of a mouse model of X-linked myotubular myopathy |
| title_full_unstemmed | Natural history of a mouse model of X-linked myotubular myopathy |
| title_short | Natural history of a mouse model of X-linked myotubular myopathy |
| title_sort | natural history of a mouse model of x linked myotubular myopathy |
| topic | mice myotubularin myotubular myopathy muscle disease natural history |
| url | http://dmm.biologists.org/content/15/7/dmm049342 |
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