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A Novel Class of FKBP12 Ligands Rescues Premature Aging Phenotypes Associated with Myotonic Dystrophy Type 1
Mikel García-Puga1,2,3,4, Gorka Gerenu2,3,5, Ariadna Bargiela6,7,8
1Cellular Oncology Group, Biogipuzkoa Health Research Institute, Paseo Dr. Beguiristain s/n, 20014 San Sebastian, Spain.
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.
Insights
New FKBP12 ligands (MP compounds) show promise for treating myotonic dystrophy type 1 (DM1). These compounds normalize calcium and redox balance, reversing aging phenotypes and improving cellular function in DM1 models.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Myotonic dystrophy type 1 (DM1) is an inherited disorder causing muscle weakness and multi-system degeneration.
- DM1 is linked to CTG expansion and MBLN decrease, leading to calcium and redox imbalance and premature aging.
- Oxidative stress exacerbates DM1 phenotypes, highlighting the need for therapeutic interventions.
Purpose of the Study:
- To investigate the therapeutic potential of novel FKBP12 ligands (MP compounds) in DM1.
- To assess the ability of MP compounds to stabilize FKBP12-ryanodine receptor interactions and correct calcium dysregulation.
- To evaluate the efficacy of MP compounds in preclinical models of DM1.
Main Methods:
- Functional studies on human DM1 fibroblasts (viability, proliferation, metabolism).
- RNA sequencing to analyze gene expression changes in treated cells.
- In vivo studies using a Drosophila model for locomotor activity and longevity.
Main Results:
- MP compounds reversed oxidative stress, improved cell viability, proliferation, mitochondrial activity, and metabolism in DM1 fibroblasts.
- RNA sequencing confirmed restoration of calcium/redox homeostasis, cell cycle, metabolism, and alternative splicing.
- MP compounds significantly extended lifespan and improved locomotor activity in a Drosophila DM1 model.
Conclusions:
- MP compounds effectively rescue multiple premature aging phenotypes in DM1 models.
- This new class of compounds demonstrates significant therapeutic potential in the preclinical setting of DM1.
- MP compounds offer a promising strategy for addressing the complex pathophysiology of DM1.
