Physiological impact and disease reversion for the severe form of centronuclear myopathy linked to dynamin
| Autor: | Roberto Silva-Rojas, Xènia Massana Muñoz, Christine Kretz, Julien Ochala, Norma B. Romero, Belinda S. Cowling, Jocelyn Laporte, Alexia Menuet |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine GTPase macromolecular substances Therapeutics Mitochondrion Biology medicine.disease_cause Muscle biology Dynamin II Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Myocyte Centronuclear myopathy Muscle Skeletal Autosomal dominant centronuclear myopathy Dynamin Mice Knockout Mice Inbred BALB C Mutation General Medicine Neuromuscular disease Oligonucleotides Antisense medicine.disease Mitochondria 3. Good health Cell biology Mice Inbred C57BL DNM2 030104 developmental biology 030220 oncology & carcinogenesis Muscle Medicine Female Research Article Genetic diseases Myopathies Structural Congenital |
| Zdroj: | JCI Insight, Vol 5, Iss 18 (2020) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | Classical dynamins are large GTPases regulating membrane and cytoskeleton dynamics, and they are linked to different pathological conditions ranging from neuromuscular diseases to encephalopathy and cancer. Dominant dynamin 2 (DNM2) mutations lead to either mild adult onset or severe autosomal dominant centronuclear myopathy (ADCNM). Our objectives were to better understand the pathomechanism of severe ADCNM and test a potential therapy. Here, we created the Dnm2SL/+ mouse line harboring the common S619L mutation found in patients with severe ADCNM and impairing the conformational switch regulating dynamin self-assembly and membrane remodeling. The Dnm2SL/+ mouse faithfully reproduces severe ADCNM hallmarks with early impaired muscle function and force, together with myofiber hypotrophy. It revealed swollen mitochondria lacking cristae as the main ultrastructural defect and potential cause of the disease. Patient analysis confirmed this structural hallmark. In addition, DNM2 reduction with antisense oligonucleotides after disease onset efficiently reverted locomotor and force defects after only 3 weeks of treatment. Most histological defects including mitochondria alteration were partially or fully rescued. Overall, this study highlights an efficient approach to revert the severe form of dynamin-related centronuclear myopathy. These data also reveal that the dynamin conformational switch is key for muscle function and should be targeted for future therapeutic developments. The dynamin 2 S619L mouse model displays defects in skeletal muscle that are rescued by reducing dynamin 2 protein levels with antisense oligonucleotide treatment. |
| Databáze: | OpenAIRE |
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