A Novel Class of FKBP12 Ligands Rescues Premature Aging Phenotypes Associated with Myotonic Dystrophy Type 1
Year: 2024
Type: article
Abstract: Background: 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.
Source: Cells
Institutions: Universidad Pública de Navarra (UPNA), Biomedical Research Networking Center on Neurodegenerative Diseases, Biogipuzkoa Health Research Institute, Ikerbasque, Universitat de València, Centre for Biomedical Network Research on Rare Diseases, INCLIVA Health Research Institute, University of the Basque Country, Universidad de Deusto, Osakidetza, Donostiako Unibertsitate Ospitalea, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,069
Awards: G2029797354, G2750602563, G2824107493, G3991824213, G4115324067, Identificación de la función y la relevancia clínica de SOX2 en envejecimiento y enfermedades asociadas al envejecimiento, DETERMINACIÓN DE LA FUNCIÖN Y RELEVANCIA CLNICA DEL REGULADOR DE CELULAS MADRE SOX9 EN ENVEJECIMIENTO Y ENFERMEDADES ASOCIADAS, Nuevos enfoques terapéuticos en la distrofia miotónica tipo 1 dirigidos a la unfolded protein response y la senescencia en modelos preclínicos, G7523278521
OpenAlex ID: W4404610560