Senescence plays a role in myotonic dystrophy type 1
Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of an accelerated aging process. However, the molecular m...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.159357 |
| _version_ | 1797634344321286144 |
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| author | Mikel García-Puga Ander Saenz-Antoñanzas Gorka Gerenu Alex Arrieta-Legorburu Roberto Fernández-Torrón Miren Zulaica Amets Saenz Joseba Elizazu Gisela Nogales-Gadea Shahinaz M. Gadalla Marcos J. Araúzo-Bravo Adolfo López de Munain Ander Matheu |
| author_facet | Mikel García-Puga Ander Saenz-Antoñanzas Gorka Gerenu Alex Arrieta-Legorburu Roberto Fernández-Torrón Miren Zulaica Amets Saenz Joseba Elizazu Gisela Nogales-Gadea Shahinaz M. Gadalla Marcos J. Araúzo-Bravo Adolfo López de Munain Ander Matheu |
| author_sort | Mikel García-Puga |
| collection | DOAJ |
| description | Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of an accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. Transcriptomic analysis of fibroblasts derived from patients with DM1 and healthy individuals revealed a decrease in cell cycle activity, cell division, and DNA damage response in DM1, all of which related to the accumulation of cellular senescence. The data from transcriptome analyses were corroborated in human myoblasts and blood samples, as well as in mouse and Drosophila models of the disease. Serial passage studies in vitro confirmed the accelerated increase in senescence and the acquisition of a senescence-associated secretory phenotype in DM1 fibroblasts, whereas the DM1 Drosophila model showed reduced longevity and impaired locomotor activity. Moreover, functional studies highlighted the impact of BMI1 and downstream p16INK4A/RB and ARF/p53/p21CIP pathways in DM1-associated cellular phenotypes. Importantly, treatment with the senolytic compounds Quercetin, Dasatinib, or Navitoclax reversed the accelerated aging phenotypes in both DM1 fibroblasts in vitro and in Drosophila in vivo. Our results identify the accumulation of senescence as part of DM1 pathophysiology and, therefore, demonstrate the efficacy of senolytic compounds in the preclinical setting. |
| first_indexed | 2024-03-11T12:07:19Z |
| format | Article |
| id | doaj.art-21e2c0c19010444fa4506a0c73f02c75 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:19Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-21e2c0c19010444fa4506a0c73f02c752023-11-07T16:24:39ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-10-01719Senescence plays a role in myotonic dystrophy type 1Mikel García-PugaAnder Saenz-AntoñanzasGorka GerenuAlex Arrieta-LegorburuRoberto Fernández-TorrónMiren ZulaicaAmets SaenzJoseba ElizazuGisela Nogales-GadeaShahinaz M. GadallaMarcos J. Araúzo-BravoAdolfo López de MunainAnder MatheuMyotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of an accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. Transcriptomic analysis of fibroblasts derived from patients with DM1 and healthy individuals revealed a decrease in cell cycle activity, cell division, and DNA damage response in DM1, all of which related to the accumulation of cellular senescence. The data from transcriptome analyses were corroborated in human myoblasts and blood samples, as well as in mouse and Drosophila models of the disease. Serial passage studies in vitro confirmed the accelerated increase in senescence and the acquisition of a senescence-associated secretory phenotype in DM1 fibroblasts, whereas the DM1 Drosophila model showed reduced longevity and impaired locomotor activity. Moreover, functional studies highlighted the impact of BMI1 and downstream p16INK4A/RB and ARF/p53/p21CIP pathways in DM1-associated cellular phenotypes. Importantly, treatment with the senolytic compounds Quercetin, Dasatinib, or Navitoclax reversed the accelerated aging phenotypes in both DM1 fibroblasts in vitro and in Drosophila in vivo. Our results identify the accumulation of senescence as part of DM1 pathophysiology and, therefore, demonstrate the efficacy of senolytic compounds in the preclinical setting.https://doi.org/10.1172/jci.insight.159357AgingCell biology |
| spellingShingle | Mikel García-Puga Ander Saenz-Antoñanzas Gorka Gerenu Alex Arrieta-Legorburu Roberto Fernández-Torrón Miren Zulaica Amets Saenz Joseba Elizazu Gisela Nogales-Gadea Shahinaz M. Gadalla Marcos J. Araúzo-Bravo Adolfo López de Munain Ander Matheu Senescence plays a role in myotonic dystrophy type 1 JCI Insight Aging Cell biology |
| title | Senescence plays a role in myotonic dystrophy type 1 |
| title_full | Senescence plays a role in myotonic dystrophy type 1 |
| title_fullStr | Senescence plays a role in myotonic dystrophy type 1 |
| title_full_unstemmed | Senescence plays a role in myotonic dystrophy type 1 |
| title_short | Senescence plays a role in myotonic dystrophy type 1 |
| title_sort | senescence plays a role in myotonic dystrophy type 1 |
| topic | Aging Cell biology |
| url | https://doi.org/10.1172/jci.insight.159357 |
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