Alterations of redox dynamics and desmin post-translational modifications in skeletal muscle models of desminopathies
| Autor: | Meng-Er Huang, Guilhem Clary, Sabrina Batonnet-Pichon, Florence Delort, Fany Bourgois-Rocha, Eva Cabet, Onnik Agbulut, Alain Lilienbaum, Coralie Hakibilen, Patrick Vicart, Bertrand-David Segard |
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| Přispěvatelé: | Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stress génotoxiques et cancer, Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7) |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male intermediate filaments Mutant Muscle Proteins Mice Transgenic Oxidative phosphorylation [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] Biology Protein aggregation medicine.disease_cause Antioxidants Muscular Dystrophies Desmin 03 medical and health sciences Mice 0302 clinical medicine N-acetyl-L-cysteine medicine Intermediate Filament Protein Animals Homeostasis Humans Intermediate filament Muscle Skeletal Cells Cultured aggregation Skeletal muscle Cell Biology Cell biology Mice Inbred C57BL Disease Models Animal Oxidative Stress 030104 developmental biology medicine.anatomical_structure Amino Acid Substitution 030220 oncology & carcinogenesis myopathies Mutant Proteins Cardiomyopathies Oxidation-Reduction Protein Processing Post-Translational Oxidative stress |
| Zdroj: | Experimental Cell Research Experimental Cell Research, Elsevier, 2019, 383 (2), pp.111539. ⟨10.1016/j.yexcr.2019.111539⟩ |
| ISSN: | 1090-2422 0014-4827 |
| DOI: | 10.1016/j.yexcr.2019.111539⟩ |
| Popis: | International audience; Desminopathies are a type of myofibrillar myopathy resulting from mutations in DES, encoding the intermediate filament protein desmin. They display heterogeneous phenotypes, suggesting environment influences. Patient muscle proteins show oxidative features linking oxidative stress, protein aggregation, and abnormal protein deposition. To improve understanding of redox balance in desminopathies, we further developed cellular models of four pathological mutants localized in 2B helical domain (the most important region for desmin polymerization) to explore desmin behavior upon oxidative stress. We show that the mutations desQ389P and desD399Y share common stress-induced aggregates, desR406W presents more scattered cytoplasmic aggregative pattern, and pretreatment with N-acetyl-l-cysteine (NAC), an antioxidant molecule, prevents all type of aggregation. Mutants desD399Y and desR406W had delayed oxidation kinetics following H2O2 stress prevented by NAC pretreatment. Further, we used AAV-injected mouse models to confirm in vivo effects of N-acetyl-l-cysteine. AAV-desD399Y-injected muscles displayed similar physio-pathological characteristics as observed in patients. However, after 2 months of NAC treatment, they did not have reduced aggregates. Finally, in both models, stress induced some post-translational modifications changing Isoelectric Point, such as potential hyperphosphorylations, and/or molecular weight of human desmin by proteolysis. However, each mutant presented its own pattern that seemed to be post-aggregative. In conclusion, our results indicate that individual desmin mutations have unique pathological molecular mechanisms partly linked to alteration of redox homeostasis. Integrating these mutant-specific behaviors will be important when considering future |
| Databáze: | OpenAIRE |
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