Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances
Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the <i>MTM1</i> gene encoding the phosphoinositide phosphatase myot...
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| Language: | English |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/21/11377 |
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| author | Raquel Gómez-Oca Belinda S. Cowling Jocelyn Laporte |
| author_facet | Raquel Gómez-Oca Belinda S. Cowling Jocelyn Laporte |
| author_sort | Raquel Gómez-Oca |
| collection | DOAJ |
| description | Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the <i>MTM1</i> gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the <i>DNM2</i> gene encoding the mechanoenzyme dynamin 2, the <i>BIN1</i> gene encoding the membrane curvature sensing amphiphysin 2, and the <i>RYR1</i> gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets. |
| first_indexed | 2024-03-10T06:02:18Z |
| format | Article |
| id | doaj.art-08539916a47a4d8389490e8ecf59e350 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:02:18Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-08539916a47a4d8389490e8ecf59e3502023-11-22T20:51:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211137710.3390/ijms222111377Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment AdvancesRaquel Gómez-Oca0Belinda S. Cowling1Jocelyn Laporte2Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, FranceDynacure, 67400 Illkirch, FranceDepartment of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, FranceCentronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the <i>MTM1</i> gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the <i>DNM2</i> gene encoding the mechanoenzyme dynamin 2, the <i>BIN1</i> gene encoding the membrane curvature sensing amphiphysin 2, and the <i>RYR1</i> gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.https://www.mdpi.com/1422-0067/22/21/11377centronuclear myopathymyotubular myopathymyotubularindynaminamphiphysinryanodine receptor |
| spellingShingle | Raquel Gómez-Oca Belinda S. Cowling Jocelyn Laporte Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances International Journal of Molecular Sciences centronuclear myopathy myotubular myopathy myotubularin dynamin amphiphysin ryanodine receptor |
| title | Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances |
| title_full | Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances |
| title_fullStr | Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances |
| title_full_unstemmed | Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances |
| title_short | Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances |
| title_sort | common pathogenic mechanisms in centronuclear and myotubular myopathies and latest treatment advances |
| topic | centronuclear myopathy myotubular myopathy myotubularin dynamin amphiphysin ryanodine receptor |
| url | https://www.mdpi.com/1422-0067/22/21/11377 |
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