Cargando…

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(2+)) mishandling. Ca(2+) release from the sarcoplasmic...

Descripción completa

Detalles Bibliográficos
Autores principales: Meyer, Pierre, Notarnicola, Cécile, Meli, Albano C., Matecki, Stefan, Hugon, Gérald, Salvador, Jérémy, Khalil, Mirna, Féasson, Léonard, Cances, Claude, Cottalorda, Jérôme, Desguerre, Isabelle, Cuisset, Jean-Marie, Sabouraud, Pascal, Lacampagne, Alain, Chevassus, Hugues, Rivier, François, Carnac, Gilles
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657486/
https://www.ncbi.nlm.nih.gov/pubmed/34884796
http://dx.doi.org/10.3390/ijms222312985
_version_ 1784612514853552128
author Meyer, Pierre
Notarnicola, Cécile
Meli, Albano C.
Matecki, Stefan
Hugon, Gérald
Salvador, Jérémy
Khalil, Mirna
Féasson, Léonard
Cances, Claude
Cottalorda, Jérôme
Desguerre, Isabelle
Cuisset, Jean-Marie
Sabouraud, Pascal
Lacampagne, Alain
Chevassus, Hugues
Rivier, François
Carnac, Gilles
author_facet Meyer, Pierre
Notarnicola, Cécile
Meli, Albano C.
Matecki, Stefan
Hugon, Gérald
Salvador, Jérémy
Khalil, Mirna
Féasson, Léonard
Cances, Claude
Cottalorda, Jérôme
Desguerre, Isabelle
Cuisset, Jean-Marie
Sabouraud, Pascal
Lacampagne, Alain
Chevassus, Hugues
Rivier, François
Carnac, Gilles
author_sort Meyer, Pierre
collection PubMed
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(2+)) mishandling. Ca(2+) 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(2+) 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 RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca(2+) concentration was increased, but RYR1-mediated Ca(2+) release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca(2+) 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(2+) 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(2+) leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.
format Online
Article
Text
id pubmed-8657486
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-86574862021-12-10 Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients Meyer, Pierre Notarnicola, Cécile Meli, Albano C. Matecki, Stefan Hugon, Gérald Salvador, Jérémy Khalil, Mirna Féasson, Léonard Cances, Claude Cottalorda, Jérôme Desguerre, Isabelle Cuisset, Jean-Marie Sabouraud, Pascal Lacampagne, Alain Chevassus, Hugues Rivier, François Carnac, Gilles Int J Mol Sci Article 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(2+)) mishandling. Ca(2+) 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(2+) 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 RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca(2+) concentration was increased, but RYR1-mediated Ca(2+) release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca(2+) 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(2+) 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(2+) leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD. MDPI 2021-11-30 /pmc/articles/PMC8657486/ /pubmed/34884796 http://dx.doi.org/10.3390/ijms222312985 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Meyer, Pierre
Notarnicola, Cécile
Meli, Albano C.
Matecki, Stefan
Hugon, Gérald
Salvador, Jérémy
Khalil, Mirna
Féasson, Léonard
Cances, Claude
Cottalorda, Jérôme
Desguerre, Isabelle
Cuisset, Jean-Marie
Sabouraud, Pascal
Lacampagne, Alain
Chevassus, Hugues
Rivier, François
Carnac, Gilles
Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657486/
https://www.ncbi.nlm.nih.gov/pubmed/34884796
http://dx.doi.org/10.3390/ijms222312985
work_keys_str_mv AT meyerpierre skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT notarnicolacecile skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT melialbanoc skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT mateckistefan skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT hugongerald skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT salvadorjeremy skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT khalilmirna skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT feassonleonard skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT cancesclaude skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT cottalordajerome skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT desguerreisabelle skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT cuissetjeanmarie skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT sabouraudpascal skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT lacampagnealain skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT chevassushugues skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT rivierfrancois skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients
AT carnacgilles skeletalryanodinereceptorsareinvolvedinimpairedmyogenicdifferentiationinduchennemusculardystrophypatients