Natural history of a mouse model of X-linked myotubular myopathy.

Autor:	Sarikaya E; Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada., Sabha N; Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada., Volpatti J; Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada., Pannia E; Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada., Maani N; Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada., Gonorazky HD; Division of Neurology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada., Celik A; Centre for Computational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada., Liang Y; Centre for Computational Medicine, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada., Onofre-Oliveira P; Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada., Dowling JJ; Program for Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.; Division of Neurology, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 1X8, Canada.; Paediatrics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2022 Jul 01; Vol. 15 (7). Date of Electronic Publication: 2022 Jul 25.
DOI:	10.1242/dmm.049342
Abstrakt:	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. Competing Interests: Competing interests J.J.D. has sponsored research agreements with Astellas Gene Therapy and Dynacure. None of the research in this study was performed as part of these agreements. For all other authors, there are no competing or financial interests. (© 2022. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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