Reconditionnement musculaire dans un modèle murin de myopathie centronucléaire autosomique dominante par inactivation du gène myostatine

Abstract : Autosomal dominant centronuclear myopathy (AD-CNM) is a rare congenital muscle disease caused by mutations predominantly found in the dynamin 2 gene (DNM2). The clinical features generally reported are progressive muscle atrophy and weakness. To date, no treatment is available. The mouse model for AD-CNM harboring a mutation of the dynamin-2 gene (KI-Dnm2R465W/+) reproduces some of the human clinical features, notably muscle atrophy and weakness. Mstn, is a master negative regulator of skeletal muscle mass. We hypothesized that inactivation of mstn could limit muscle atrophy and weakness reported in the AD-CNM mouse model (KI-dnm2R465W/+). To test this hypothesis, we intercrossed KI-Dnm2R465W/+ mice with mice inactivated for mstn (KO-mstn) to generate a double mutated lineage (KIKO). The present study demonstrates that mstn gene inactivation allows for an improvement of muscle weight and volume, prevents muscle weakness and motor skill alterations. Our data also reveal that inactivation of mstn essentially downregulates some actors implicated in the catabolic ubiquitin-proteasome system. Furthermore, we show that inactivation of mstn decreases the frequency of of histological abnormalities characteristical in KI mice. We hypothesize that these abnormalities could be due to an alteration of mitochondrial function and network. The perspective to this work is to verify this hypothesis in the mouse model, which will contribute to a better understanding of the physiopathological mechanisms and can open new insight in the therapeutical approach to AD-CNM.
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Submitted on : Tuesday, March 12, 2019 - 5:30:41 PM
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David Arnould. Reconditionnement musculaire dans un modèle murin de myopathie centronucléaire autosomique dominante par inactivation du gène myostatine. Médecine humaine et pathologie. Université de Lyon, 2018. Français. ⟨NNT : 2018LYSES008⟩. ⟨tel-02065543⟩

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