Potential compensatory mechanisms preserving cardiac function in myotubular myopathy.

Autor: Simon A; Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 1 rue Laurent Fries, Illkirch, 67404, France., Diedhiou N; Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 1 rue Laurent Fries, Illkirch, 67404, France., Reiss D; Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 1 rue Laurent Fries, Illkirch, 67404, France., Goret M; Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 1 rue Laurent Fries, Illkirch, 67404, France., Grandgirard E; Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 1 rue Laurent Fries, Illkirch, 67404, France., Laporte J; Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, 1 rue Laurent Fries, Illkirch, 67404, France. jocelyn@igbmc.fr.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 Dec 03; Vol. 81 (1), pp. 476. Date of Electronic Publication: 2024 Dec 03.
DOI: 10.1007/s00018-024-05512-9
Abstrakt: X-Linked myotubular myopathy (XLMTM) is characterized by severe skeletal muscle weakness and reduced life expectancy. The pathomechanism and the impact of non-muscular defects affecting survival, such as liver dysfunction, are poorly understood. Here, we investigated organ-specific effects of XLMTM using the Mtm1 -/y mouse model. We performed RNA-sequencing to identify a common mechanism in different skeletal muscles, and to explore potential phenotypes and compensatory mechanisms in the heart and the liver. The cardiac and hepatic function and structural integrity were assessed both in vivo and in vitro. Our findings revealed no defects in liver function or morphology. A disease signature common to several skeletal muscles highlighted dysregulation of muscle development, inflammation, cell adhesion and oxidative phosphorylation as key pathomechanisms. The heart displayed only mild functional alterations without obvious structural defects. Transcriptomic analyses revealed an opposite dysregulation of mitochondrial function, cell adhesion and beta integrin trafficking pathways in cardiac muscle compared to skeletal muscles. Despite this dysregulation, biochemical and cellular experiments demonstrated that these pathways were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data suggest a compensatory mechanism preserving cardiac function, pointing to potential therapeutic targets to cure the severe skeletal muscle defects in XLMTM.
Competing Interests: Declarations. Ethics approval: All procedures involving animals followed the European directive 2010/63/EU of September 22, 2010, and ethical approval was granted by the Ethics Committee of the French ministry for Research (APAFIS#4469-2016031110589922, APAFIS #35398-2022021019049942). Competing interests: The authors have no relevant financial or non-financial interests to disclose.
(© 2024. The Author(s).)
Databáze: MEDLINE
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