Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies
Desminopathies belong to a family of muscle disorders called myofibrillar myopathies that are caused by Desmin mutations and lead to protein aggregates in muscle fibers. To date, the initial pathological steps of desminopathies and the impact of desmin aggregates in the genesis of the disease are un...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715005227 |
| _version_ | 1818020928835026944 |
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| author | Caroline Ramspacher Emily Steed Francesco Boselli Rita Ferreira Nathalie Faggianelli Stéphane Roth Coralie Spiegelhalter Nadia Messaddeq Le Trinh Michael Liebling Nikhil Chacko Federico Tessadori Jeroen Bakkers Jocelyn Laporte Karim Hnia Julien Vermot |
| author_facet | Caroline Ramspacher Emily Steed Francesco Boselli Rita Ferreira Nathalie Faggianelli Stéphane Roth Coralie Spiegelhalter Nadia Messaddeq Le Trinh Michael Liebling Nikhil Chacko Federico Tessadori Jeroen Bakkers Jocelyn Laporte Karim Hnia Julien Vermot |
| author_sort | Caroline Ramspacher |
| collection | DOAJ |
| description | Desminopathies belong to a family of muscle disorders called myofibrillar myopathies that are caused by Desmin mutations and lead to protein aggregates in muscle fibers. To date, the initial pathological steps of desminopathies and the impact of desmin aggregates in the genesis of the disease are unclear. Using live, high-resolution microscopy, we show that Desmin loss of function and Desmin aggregates promote skeletal muscle defects and alter heart biomechanics. In addition, we show that the calcium dynamics associated with heart contraction are impaired and are associated with sarcoplasmic reticulum dilatation as well as abnormal subcellular distribution of Ryanodine receptors. Our results demonstrate that desminopathies are associated with perturbed excitation-contraction coupling machinery and that aggregates are more detrimental than Desmin loss of function. Additionally, we show that pharmacological inhibition of aggregate formation and Desmin knockdown revert these phenotypes. Our data suggest alternative therapeutic approaches and further our understanding of the molecular determinants modulating Desmin aggregate formation. |
| first_indexed | 2024-04-14T08:12:04Z |
| format | Article |
| id | doaj.art-ab4d13b42d0e4f85a7dfd79d3cf519e3 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-14T08:12:04Z |
| publishDate | 2015-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ab4d13b42d0e4f85a7dfd79d3cf519e32022-12-22T02:04:32ZengElsevierCell Reports2211-12472015-06-0111101564157610.1016/j.celrep.2015.05.010Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for DesminopathiesCaroline Ramspacher0Emily Steed1Francesco Boselli2Rita Ferreira3Nathalie Faggianelli4Stéphane Roth5Coralie Spiegelhalter6Nadia Messaddeq7Le Trinh8Michael Liebling9Nikhil Chacko10Federico Tessadori11Jeroen Bakkers12Jocelyn Laporte13Karim Hnia14Julien Vermot15Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceMolecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USADepartment of Electrical and Computer Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USADepartment of Electrical and Computer Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USAHubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht 3584 CT, the NetherlandsHubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht 3584 CT, the NetherlandsInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, FranceDesminopathies belong to a family of muscle disorders called myofibrillar myopathies that are caused by Desmin mutations and lead to protein aggregates in muscle fibers. To date, the initial pathological steps of desminopathies and the impact of desmin aggregates in the genesis of the disease are unclear. Using live, high-resolution microscopy, we show that Desmin loss of function and Desmin aggregates promote skeletal muscle defects and alter heart biomechanics. In addition, we show that the calcium dynamics associated with heart contraction are impaired and are associated with sarcoplasmic reticulum dilatation as well as abnormal subcellular distribution of Ryanodine receptors. Our results demonstrate that desminopathies are associated with perturbed excitation-contraction coupling machinery and that aggregates are more detrimental than Desmin loss of function. Additionally, we show that pharmacological inhibition of aggregate formation and Desmin knockdown revert these phenotypes. Our data suggest alternative therapeutic approaches and further our understanding of the molecular determinants modulating Desmin aggregate formation.http://www.sciencedirect.com/science/article/pii/S2211124715005227 |
| spellingShingle | Caroline Ramspacher Emily Steed Francesco Boselli Rita Ferreira Nathalie Faggianelli Stéphane Roth Coralie Spiegelhalter Nadia Messaddeq Le Trinh Michael Liebling Nikhil Chacko Federico Tessadori Jeroen Bakkers Jocelyn Laporte Karim Hnia Julien Vermot Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies Cell Reports |
| title | Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies |
| title_full | Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies |
| title_fullStr | Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies |
| title_full_unstemmed | Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies |
| title_short | Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies |
| title_sort | developmental alterations in heart biomechanics and skeletal muscle function in desmin mutants suggest an early pathological root for desminopathies |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715005227 |
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