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Rôle des cellules souches musculaires dans la physiopathologie de l’amyotrophie spinale

Abstract : Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neurons (MN) degeneration, muscle atrophy and paralysis leading to premature death in the most severe forms. SMA is due to a reduction of the ubiquitous protein called SMN resulting from homozygous mutations in SMN1 gene. Long considered as a purely neuronal disease, SMA appears now as a multisystemic disease affecting many peripheral tissues, including skeletal muscle and muscle stem cells (SC). With the first successes of AAV9-SMN-based gene therapy, uncertainties emerge about the long-term effects of these therapies, particularly regarding the integrity of the neuromuscular system. This work is in line with this problematic, and shed new light on the involvement of muscle SC in SMA pathophysiology. We observed a decreased number of SC in the muscles of SMA Type II patients, which could result from reduced ability of SMN-deficient SC to commit to quiescence and a loss of quiescent SC by apoptosis. Using the murine conditional KO model Pax7CreERT2/+;SmnF7/F7, we demonstrated that this SC-depletion induced by SMN deficiency leads, in the long term, to a selective loss of α-MN and phenotypic changes in muscle fibers. Finally, we showed a deregulation of miRNA expression profile in SMA mouse SC, and identified potential new therapeutic targets for the development of future combined therapeutic strategies, restoring SMN and preserving the neuromuscular system in the long term.
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Submitted on : Thursday, October 15, 2020 - 4:30:08 PM
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  • HAL Id : tel-02968362, version 1

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Jordan Mecca. Rôle des cellules souches musculaires dans la physiopathologie de l’amyotrophie spinale. Biologie cellulaire. Sorbonne Université, 2019. Français. ⟨NNT : 2019SORUS261⟩. ⟨tel-02968362⟩

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