Physiological impact and disease reversion for the severe form of centronuclear myopathy linked to dynamin
Xènia Massana Muñoz, Christine Kretz, Roberto Silva-Rojas, Julien Ochala, Alexia Menuet, Norma B. Romero, Belinda S. Cowling, Jocelyn Laporte
Xènia Massana Muñoz, Christine Kretz, Roberto Silva-Rojas, Julien Ochala, Alexia Menuet, Norma B. Romero, Belinda S. Cowling, Jocelyn Laporte
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Research Article Muscle biology Therapeutics

Physiological impact and disease reversion for the severe form of centronuclear myopathy linked to dynamin

Abstract

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.

Authors

Xènia Massana Muñoz, Christine Kretz, Roberto Silva-Rojas, Julien Ochala, Alexia Menuet, Norma B. Romero, Belinda S. Cowling, Jocelyn Laporte

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Figure 6

DNM2 reduction reverts the motor defects of the Dnm2SL/+ mice.

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DNM2 reduction reverts the motor defects of the Dnm2SL/+ mice. (A–D) Bod...
(A–D) Body weight (5 ≤ n ≤ 11; 1-way ANOVA with Tukey’s post hoc test) (A), TA muscle weight (5 ≤ n ≤ 7; 1-way ANOVA with Tukey’s post hoc test) (B), absolute muscle force (5 ≤ n ≤ 7; Kruskal-Wallis test with Dunn’s post hoc test) (C), and specific muscle force (5 ≤ n ≤ 7; 1-way ANOVA with Tukey’s post hoc test) (D) measured at 8w in WT and Dnm2SL/+ mice treated or not with ASO-1 antisense oligonucleotide targeting Dnm2. (E and F) Body weight and hanging performance of WT and Dnm2SL/+ mice treated or not with ASO-1 between 3 and 8 weeks (6 ≤ n ≤ 7). Blocks show groups with nonsignificant difference in hanging test performance (1-way ANOVA with Tukey’s post hoc test for each individual time point). Note the hanging performance of the treated Dnm2SL/+ mice was not statistically significant from WT from week 6. Both curves show average values ± SEM for each time point and genotype. (G–I) Absolute muscle force (Kruskal-Wallis test with Dunn’s post hoc test) (G), fiber cross-sectional area (1-way ANOVA with Tukey’s post hoc test) (H), and specific muscle force (Kruskal-Wallis test with Dunn’s post hoc test) (I) measured in single myofibers from 8-week-old WT and Dnm2SL/+ mice treated or not with ASO-1 antisense oligonucleotide targeting Dnm2 (35 ≤ n ≤ 43). ****P < 0.0001 and **P < 0.01 comparing vs. WT. $$$$P < 0.0001; $$$P < 0.001; $$P < 0.01; $P < 0.05 vs. Dnm2SL/+. Charts show individual points, with additional lines indicating mean ± SEM unless differently stated.