A novel class of FKBP12 ligands rescues premature aging phenotypes associated with myotonic dystrophy type 1

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dc.contributor.authorGarcía Puga, Mikel
dc.contributor.authorGereñu Lopetegi, Gorka
dc.contributor.authorBargiela Schönbrunn, Ariadna
dc.contributor.authorEspinosa Espinosa, Jorge
dc.contributor.authorMosqueira Martín, Laura
dc.contributor.authorSagartzazu Aizpurua, Maialen
dc.contributor.authorAizpurua Iparraguirre, Jesus Mari
dc.contributor.authorVallejo Illarramendi, Ainara
dc.contributor.author Artero Allepuz, Rubén
dc.contributor.authorLópez de Munain Arregui, Adolfo
dc.contributor.author Matheu Fernández, Ander
dc.date.accessioned2025-02-24T08:35:01Z
dc.date.available2025-02-24T08:35:01Z
dc.date.issued2024-12-01
dc.date.updated2025-02-24T08:35:01Z
dc.description.abstractBackground: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder clinically characterized by progressive muscular weakness and multisystem degeneration, which correlates with the size of CTG expansion and MBLN decrease. These changes induce a calcium and redox homeostasis imbalance in several models that recapitulate the features of premature tissue aging. In this study, we characterized the impact of a new family of FKBP12 ligands (generically named MPs or MP compounds) designed to stabilize FKBP12 binding to the ryanodine receptors and normalize calcium dysregulation under oxidative stress. Methods: Human primary fibroblasts from DM1 patients and control donors, treated with MP compounds or not, were used for functional studies of cell viability, proliferation, and metabolism. The gene expression profile in treated cells was determined using RNA sequencing. The impact of MP compounds in vivo was evaluated in a Drosophila model of the disease using locomotor activity and longevity studies. Results: The treatment with different MP compounds reversed oxidative stress and impaired cell viability and proliferation, mitochondrial activity, and metabolic defects in DM1-derived primary fibroblasts. RNA sequencing analysis confirmed the restoration of molecular pathways related to calcium and redox homeostasis and additional pathways, including the cell cycle and metabolism. This analysis also revealed the rescue of alternative splicing events in DM1 fibroblasts treated with MP compounds. Importantly, treatment with MP compounds significantly extended the lifespan and improved the locomotor activity of a Drosophila model of the DM1 disease, and restored molecular defects characteristic of the disease in vivo. Conclusions: Our results revealed that MP compounds rescue multiple premature aging phenotypes described in DM1 models and decipher the benefits of this new family of compounds in the pre-clinical setting of DM1.en
dc.description.sponsorshipMG-P and LM-M received a predoctoral fellowship from the University of the Basque Country (PIF 15/245 and PIF19/184, respectively). GG was funded by the Juan de la Cierva-Incorporación (ISCIII, IJC2019-039965-I) and IKERBASQUE (RF/2023/010) research programs. This work was supported by grants from the Instituto Salud Carlos III and the European Union (PI19/01355, PI21/00557 and PI22/01905), the Health department from Basque Country (2017222021, 2018222021, 2020333008), the Education department from Basque Country (IKUR strategy, NEURODEGENPROT), and the PROMETEO/2020/081 project from the Generalitat Valenciana and CIBERNED funds (CB06/05/1126, Group 609)en
dc.identifier.citationGarcía-Puga, M., Gerenu, G., Bargiela, A., Espinosa-Espinosa, J., Mosqueira-Martín, L., Sagartzazu-Aizpurua, M., Aizpurua, J. M., Vallejo-Illarramendi, A., Artero, R., López de Munain, A., & Matheu, A. (2024). A Novel Class of FKBP12 Ligands Rescues Premature Aging Phenotypes Associated with Myotonic Dystrophy Type 1. Cells, 13(23). https://doi.org/10.3390/CELLS13231939
dc.identifier.doi10.3390/CELLS13231939
dc.identifier.eissn2073-4409
dc.identifier.urihttps://hdl.handle.net/20.500.14454/2355
dc.language.isoeng
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)
dc.rights© 2024 by the authors
dc.subject.otherExtended longevity
dc.subject.otherFKBP12/RyR interaction
dc.subject.otherMultisystem recovery
dc.subject.otherMyotonic dystrophy
dc.subject.otherOxidative stress
dc.titleA novel class of FKBP12 ligands rescues premature aging phenotypes associated with myotonic dystrophy type 1en
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.issue23
oaire.citation.titleCells
oaire.citation.volume13
oaire.licenseConditionttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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