Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca<sup>2+</sup>) mishandling. Ca<sup>2+&...
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| author | Pierre Meyer Cécile Notarnicola Albano C. Meli Stefan Matecki Gérald Hugon Jérémy Salvador Mirna Khalil Léonard Féasson Claude Cances Jérôme Cottalorda Isabelle Desguerre Jean-Marie Cuisset Pascal Sabouraud Alain Lacampagne Hugues Chevassus François Rivier Gilles Carnac |
| author_facet | Pierre Meyer Cécile Notarnicola Albano C. Meli Stefan Matecki Gérald Hugon Jérémy Salvador Mirna Khalil Léonard Féasson Claude Cances Jérôme Cottalorda Isabelle Desguerre Jean-Marie Cuisset Pascal Sabouraud Alain Lacampagne Hugues Chevassus François Rivier Gilles Carnac |
| author_sort | Pierre Meyer |
| collection | DOAJ |
| description | Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca<sup>2+</sup>) mishandling. Ca<sup>2+</sup> release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca<sup>2+</sup> release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing <i>RYR1</i> expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca<sup>2+</sup> concentration was increased, but RYR1-mediated Ca<sup>2+</sup> release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca<sup>2+</sup> concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca<sup>2+</sup> concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca<sup>2+</sup> leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD. |
| first_indexed | 2024-03-10T04:52:34Z |
| format | Article |
| id | doaj.art-acdbf34d20f848858c629cd15c77ba00 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:52:34Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-acdbf34d20f848858c629cd15c77ba002023-11-23T02:31:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231298510.3390/ijms222312985Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy PatientsPierre Meyer0Cécile Notarnicola1Albano C. Meli2Stefan Matecki3Gérald Hugon4Jérémy Salvador5Mirna Khalil6Léonard Féasson7Claude Cances8Jérôme Cottalorda9Isabelle Desguerre10Jean-Marie Cuisset11Pascal Sabouraud12Alain Lacampagne13Hugues Chevassus14François Rivier15Gilles Carnac16PhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FranceClinical Investigation Center, Montpellier University Hospital, 34000 Montpellier, FranceMyology Unit, Reference Center for Neuromuscular Diseases Euro-NmD, Inter-University Laboratory of Human Movement Sciences—EA7424, University Hospital of Saint-Etienne, 42055 Saint-Etienne, FranceReference Center for Neuromuscular Diseases AOC, Pediatric Neurology Department, Toulouse University Hospital, 3100 Toulouse, FrancePediatric Orthopedic and Plastic Surgery Department, Montpellier University Hospital, 34295 Montpellier, FranceReference Center for Neuromuscular Diseases Paris Nord-Ile-de-France-Est, Pediatric Neurology Department, Necker Enfant Malades University Hospital, Assistance Publique des Hôpitaux de Paris Centre, Paris University, 75019 Paris, FranceReference Center for Neuromuscular Diseases Nord-Ile-de-France-Est, Pediatric Neurology Department, Lille University Hospital, 59000 Lille, FranceReference Center for Neuromuscular Diseases Nord-Ile-de-France-Est, Pediatric Neurology Department, Reims University Hospital, 51100 Reims, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FranceClinical Investigation Center, Montpellier University Hospital, 34000 Montpellier, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FrancePhyMedExp, University of Montpellier, Inserm, CNRS, 34295 Montpellier, FranceDuchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca<sup>2+</sup>) mishandling. Ca<sup>2+</sup> release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca<sup>2+</sup> release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing <i>RYR1</i> expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca<sup>2+</sup> concentration was increased, but RYR1-mediated Ca<sup>2+</sup> release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca<sup>2+</sup> concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca<sup>2+</sup> concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca<sup>2+</sup> leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.https://www.mdpi.com/1422-0067/22/23/12985Duchenne muscular dystrophyryanodine receptormyogenesisendomysial fibrosishuman |
| spellingShingle | Pierre Meyer Cécile Notarnicola Albano C. Meli Stefan Matecki Gérald Hugon Jérémy Salvador Mirna Khalil Léonard Féasson Claude Cances Jérôme Cottalorda Isabelle Desguerre Jean-Marie Cuisset Pascal Sabouraud Alain Lacampagne Hugues Chevassus François Rivier Gilles Carnac Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients International Journal of Molecular Sciences Duchenne muscular dystrophy ryanodine receptor myogenesis endomysial fibrosis human |
| title | Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients |
| title_full | Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients |
| title_fullStr | Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients |
| title_full_unstemmed | Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients |
| title_short | Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients |
| title_sort | skeletal ryanodine receptors are involved in impaired myogenic differentiation in duchenne muscular dystrophy patients |
| topic | Duchenne muscular dystrophy ryanodine receptor myogenesis endomysial fibrosis human |
| url | https://www.mdpi.com/1422-0067/22/23/12985 |
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