In vivo RyR1 reduction in muscle triggers a core-like myopathy
Abstract Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have...
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BMC
2020-11-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | http://link.springer.com/article/10.1186/s40478-020-01068-4 |
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doaj-2c59ba431b5a4681b7ca6ffbbfedcadb2020-11-25T04:09:41ZengBMCActa Neuropathologica Communications2051-59602020-11-018111810.1186/s40478-020-01068-4In vivo RyR1 reduction in muscle triggers a core-like myopathyLaurent Pelletier0Anne Petiot1Julie Brocard2Benoit Giannesini3Diane Giovannini4Colline Sanchez5Lauriane Travard6Mathilde Chivet7Mathilde Beaufils8Candice Kutchukian9David Bendahan10Daniel Metzger11Clara Franzini Armstrong12Norma B. Romero13John Rendu14Vincent Jacquemond15Julien Fauré16Isabelle Marty17INSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesCNRS, CRMBM, Aix-Marseille UnivINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesCNRS UMR5310, INSERM U1217, Institut NeuroMyoGene, University Lyon IINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesCNRS UMR5310, INSERM U1217, Institut NeuroMyoGene, University Lyon ICNRS, CRMBM, Aix-Marseille UnivCNRS UMR7104, INSERM U1258, Institut de Génétique et de Biologie Moléculaire et Cellulaire, University StrasbourgDepartment of Cell and Developmental Biology, University of PennsylvaniaNeuromuscular Morphology Unit, Center for Research in Myology, Myology Institute, Sorbonne UniversityINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesCNRS UMR5310, INSERM U1217, Institut NeuroMyoGene, University Lyon IINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesINSERM, GIN-U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, University Grenoble AlpesAbstract Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.http://link.springer.com/article/10.1186/s40478-020-01068-4Ryanodine receptorCalciumSkeletal muscleExcitation–contraction couplingCongenital myopathiesCentral core disease |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Laurent Pelletier Anne Petiot Julie Brocard Benoit Giannesini Diane Giovannini Colline Sanchez Lauriane Travard Mathilde Chivet Mathilde Beaufils Candice Kutchukian David Bendahan Daniel Metzger Clara Franzini Armstrong Norma B. Romero John Rendu Vincent Jacquemond Julien Fauré Isabelle Marty |
| spellingShingle |
Laurent Pelletier Anne Petiot Julie Brocard Benoit Giannesini Diane Giovannini Colline Sanchez Lauriane Travard Mathilde Chivet Mathilde Beaufils Candice Kutchukian David Bendahan Daniel Metzger Clara Franzini Armstrong Norma B. Romero John Rendu Vincent Jacquemond Julien Fauré Isabelle Marty In vivo RyR1 reduction in muscle triggers a core-like myopathy Acta Neuropathologica Communications Ryanodine receptor Calcium Skeletal muscle Excitation–contraction coupling Congenital myopathies Central core disease |
| author_facet |
Laurent Pelletier Anne Petiot Julie Brocard Benoit Giannesini Diane Giovannini Colline Sanchez Lauriane Travard Mathilde Chivet Mathilde Beaufils Candice Kutchukian David Bendahan Daniel Metzger Clara Franzini Armstrong Norma B. Romero John Rendu Vincent Jacquemond Julien Fauré Isabelle Marty |
| author_sort |
Laurent Pelletier |
| title |
In vivo RyR1 reduction in muscle triggers a core-like myopathy |
| title_short |
In vivo RyR1 reduction in muscle triggers a core-like myopathy |
| title_full |
In vivo RyR1 reduction in muscle triggers a core-like myopathy |
| title_fullStr |
In vivo RyR1 reduction in muscle triggers a core-like myopathy |
| title_full_unstemmed |
In vivo RyR1 reduction in muscle triggers a core-like myopathy |
| title_sort |
in vivo ryr1 reduction in muscle triggers a core-like myopathy |
| publisher |
BMC |
| series |
Acta Neuropathologica Communications |
| issn |
2051-5960 |
| publishDate |
2020-11-01 |
| description |
Abstract Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction. |
| topic |
Ryanodine receptor Calcium Skeletal muscle Excitation–contraction coupling Congenital myopathies Central core disease |
| url |
http://link.springer.com/article/10.1186/s40478-020-01068-4 |
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